Diphenylethylene compounds and uses thereof

ABSTRACT

The present invention relates to Diphenylethylene Compounds and compositions comprising a Diphenylethylene Compound. The present invention also relates to methods for preventing or treating various diseases and disorders by administering to a subject in need thereof one or more Diphenylethylene Compounds. In particular, the invention relates to methods for preventing or treating cancer or an inflammatory disorder by administering to a subject in need thereof one or more Diphenylethylene Compounds. The present invention further relates to articles of manufacture and kits comprising one or more Diphenylethylene Compounds.

This application claims the benefit of U.S. provisional application No.60/452,460, filed Mar. 5, 2003, the contents of which are incorporatedby reference herein in their entirety.

1 Field of the Invention

The present invention relates to Diphenylethylene Compounds andcompositions comprising a Diphenylethylene Compound. The presentinvention also relates to methods for preventing or treating variousdiseases and disorders by administering to a subject in need thereof oneor more Diphenylethylene Compounds. In particular, the invention relatesto methods for preventing or treating cancer or an inflammatory disorderby administering to a subject in need thereof one or moreDiphenylethylene Compounds. The present invention further relates tocertain compounds wherein one of the phenyl groups is replaced with aheterocycle.

2 BACKGROUND OF THE INVENTION

2.1 Microtubules

The cytoskeleton of eukaryotic cells consists of an extensive network ofmicrofilaments, microtubules and intermediate filaments. Microtubulesplay an important role in mitosis. α-, β-, and γ-tubulin subunits areeukaryotic cytoskeleton proteins that are responsible for the formationof microtubules. Microtubules are hollow cylinders which are comprisedof α,β-tubulin heterodimers, joined end-to-end along the microtubuleaxis. γ-tubulin is involved in microtubule organization. Once formed,the microtubules exist in an equilibrium, with tubulin dimers constantlybeing added to one end of the microtubule and removed from the oppositeend. This equilibrium allows for control of the length of themicrotubule and such control is essential for the microtubules to carryout their numerous functions in cells.

During cell division microtubules are responsible for transporting theset of daughter chromosomes to each individual daughter cell. Inparticular, during prophase, the DNA in the nucleus is replicated andthe two sets of genetic material are organized into the individual setsof daughter chromosomes. Toward the end of prophase, microtubules growfrom the centrosomes at either end of the dividing parent cell andtoward the two identical sets of chromosomes. This growing bundle ofmicrotubules forms a structure known as the mitotic spindle. Duringprometaphase, the microtubules attach themselves to the chromosomes, andupon entry into anaphase, the microtubules destabilize and shorten,drawing the daughter chromosomes apart to their respective daughtercells at opposite ends of the dividing cell. Thus, microtubules areintimately involved with the cell division process.

2.2 Cancer and Neoplastic Disease

Currently, cancer therapy involves surgery, chemotherapy and/orradiation treatment to eradicate neoplastic cells in a patient (see, forexample, Stockdale, 1998, “Principles of Cancer Patient Management”, inScientific American: Medicine, vol. 3, Rubenstein and Federman, eds.,Chapter 12, Section IV). All of these approaches pose significantdrawbacks for the patient. Surgery, for example, can be contraindicateddue to the health of the patient or can be unacceptable to the patient.Additionally, surgery might not completely remove the neoplastic tissue.Radiation therapy is effective only when the irradiated neoplastictissue exhibits a higher sensitivity to radiation than normal tissue,and radiation therapy often elicits serious side effects. (Id.)

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of neoplastic disease. Specific examplesof chemotherapeutic agents include drugs that target tubulin (e.g.,inhibit tubulin polymerization or stability or tubulin stability) ormicrotubules such as colchicine (an alkaloid extracted from the meadowsuffron), the vinca alkaloids (e.g., vincristine, vinblastine andvinorlbine) and the taxanes (e.g., paclitaxel (Taxol®) and docetaxel(Taxotere®)). Colchicine exerts its cytotoxic effect by binding to thetubulin heterodimer at a single high-affinity binding site known as thecolchicine site. This binding induces an alteration in the structure ofthe dimer and hinders the assembly of the dimers into microtubules. Thecolchicine binding site displays affinity for a diverse group ofmolecular structures, including, but not limited to, thepodophyllotoxins, steganacin, the chalcones, nocodazole and TN-16.Exposure of rapidly dividing cells such as cancer cells to Colchicinecauses the disappearance of the mitotic spindle and blocks the cells inM phase of the cell cyle and eventually kills the cells. The vincaalkaloids bind to a site on β-tubulin known as the vinca alkaloidbinding site, resulting in a destabilization of the tubulin dimers. Thepoisoned dimers can then be incorporated into the microtubule polymerand prevent further growth of the microtubule. The taxanes bind directlyto tubulin subunits of intact microtubules, stabilize the microtubules,and inhibit depolymerization or stability. When the dividing cell entersanaphase, the stabilized microtubules are prevented from contracting andare not able to draw each set of daughter chromosomes to theirrespective daughter cells. Thus, cell division cannot take place and thecells are blocked in M phase of the cell cycle and eventually apoptosisresults.

Despite the availability of a variety of chemotherapeutic agents,traditional chemotherapy has many drawbacks (see, for example,Stockdale, 1998, “Principles Of Cancer Patient Management” in ScientificAmerican Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect.10). Almost all chemotherapeutic agents are toxic, and chemotherapy cancause significant, and often dangerous, side effects, including severenausea, bone marrow depression, immunosuppression, etc. Additionally,many tumor cells are resistant or develop resistance to chemotherapeuticagents through multi-drug resistance. Therefore, there is a significantneed in the art for novel compounds, compositions, and methods that areuseful for treating cancer or neoplastic disease with minimal or no sideeffects. Further, there is a need for cancer treatments that providecancer-cell-specific therapies with increased specificity and decreasedtoxicity.

2.3 Inflammatory Disorders

Inflammation plays a fundamental role in host defenses and theprogression of immune-mediated diseases. The inflammatory response isinitiated in response to injury (e.g., trauma, ischemia, and foreignparticles) and infection (e.g., bacterial or viral infection) by acomplex cascade of events, including chemical mediators (e.g., cytokinesand prostaglandins) and inflammatory cells (e.g., leukocytes). Theinflammatory response is characterized by increased blood flow,increased capillary permeability, and the influx of phagocytic cells.These events result in swelling, redness, warmth (altered heatpatterns), and pus formation at the site of injury or infection.

Cytokines and prostaglandins control the inflammatory response, and arereleased in an ordered and self-limiting cascade into the blood oraffected tissues. This release of cytokines and prostaglandins increasesthe blood flow to the area of injury or infection, and may result inredness and warmth. Some of these chemicals cause a leak of fluid intothe tissues, resulting in swelling. This protective process maystimulate nerves and cause pain. These changes, when occurring for alimited period in the relevant area, work to the benefit of the body.

A delicate well-balanced interplay between the humoral and cellularimmune elements in the inflammatory response enables the elimination ofharmful agents and the initiation of the repair of damaged tissue. Whenthis delicately balanced interplay is disrupted, the inflammatoryresponse may result in considerable damage to normal tissue and may bemore harmful than the original insult that initiated the reaction. Inthese cases of uncontrolled inflammatory responses, clinicalintervention is needed to prevent tissue damage and organ dysfunction.Diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease,asthma, allergies or inflammatory bowel disease, are characterized bychronic inflammation.

Current treatments for inflammatory disorders involve symptomaticmedications and immunosuppressive agents to control symptoms. Forexample, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin,ibuprofen, fenoprofen, naproxen, tolmetin, sulindac, meclofenamatesodium, piroxicam, flurbiprofen, diclofenac, oxaprozin, nabumetone,etodolac, and ketoprofen have analgesic and anti-inflammatory effects.However, NSAIDs are believed not to be capable of altering progressionof the disease. (Tiemey et al. (eds), Current Medical Diagnosis &Treatment, 37 ed., Appleton & Lange (1998), p793). Moreover, NSAIDsfrequently cause gastrointestinal side effects, affect the lowerintestinal tract causing perforation or aggravating inflammatory boweldisease, produce renal toxicity and prolong bleeding time.Corticosteroids are another class of drugs that are commonly used tocontrol inflammatory symptoms. Corticosteroids, like NSAIDs, do notalter the natural progression of the disease, and thus, clinicalmanifestations of active disease commonly reappear when the drug isdiscontinued. The serious problem of untoward reactions resulting fromprolonged corticosteroid therapy (e.g., osteoporosis, increased risk ofinfection, increased appetite, hypertension, edema, peptic ulcers,psychoses) greatly limits its long-term use.

Low doses of immunosuppressive agents such as cytotoxic agents are alsocommonly used to in treatment of inflammatory disorders. For example,methotrexate, an antagonist of folic acid, is often used in treatment ofpsoriasis, rheumatoid arthritis and other inflammatory diseases.Methotrexate, like other cytotoxic agents, frequently causes stomatitis,erythema, slopecia, nausea, vomiting, diarrhea, and damage to majororgans such kidney and liver. The long-term usage of immunosuppressiveagents usually leaves the patient defenseless to infections.

New treatments for inflammatory disorders are constantly being sought.In particular, any new treatment that reduces the dosage and/orfrequency of administration of agents currently being used, or iscapable of making a currently used treatment more effective isconstantly being sought.

2.4 Central Nervous System Disorders

Central nervous system disorders affect a wide range of the populationwith differing severity. Generally, one major feature of this class ofdisorders includes the significant impairment of cognition or memorythat represents a marked deterioration from a previous level offunctioning. Dementia, for example, is characterized by severalcognitive impairments including significant memory deficit and can standalone or be an underlying characteristic feature of a variety ofdiseases, including Alzheimer disease, Parkinson disease, Huntingtondisease, and Multiple Sclerosis to name but a few. Other central nervoussystem disorders include delerium, or disturbances in consciousness thatoccur over a short period of time, and amnestic disorder, or discreetmemory impairments that occur in the absence of other central nervoussystem impairments.

3 SUMMARY OF THE INVENTION

The present invention provides novel compounds, novel pharmaceuticalcompositions and uses of those compounds or pharmaceutical compositionsin the prevention, treatment or management of various disorders. Thepresent invention also provides new uses for previously disclosedcompounds including those disclosed in PCT International Publication No.WO 98/06692, published Feb. 19, 1998 (see, e.g., page 6, line 4 to page7, line 29) and U.S. Pat. No. 5,929,117, issued Jul. 22, 1999 (see,e.g., column 4, line 45 to column 5, line 38), each of which isincorporated by reference herein in its entirety. In particular, theinvention provides methods for preventing, managing or treating cancerincluding cancer refractory or non-responsive to conventional orcurrently available cancer therapy utilizing certain immunotherapeuticcompounds disclosed in PCT International Publication No. WO 98/06692 andU.S. Pat. No. 5,929,117.

The present invention provides compounds having formulas I-X and thoseof Table 1 forth below.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁, R₄, R₅ and X are as described herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(a), R_(b), & and R_(d) are asdescribed herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁, R₂, R₃, R, R₆, R₇, R₈, R_(c) and R_(d) are as describedherein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(c) and R_(d) are as describedherein,

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁, R₂, R₃, R₄, R₅, R₆, R₁₆, R₁₇, R_(a), R_(b), R_(c), R_(d) andn are as described herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are as described herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are as described herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are as described herein.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,wherein R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are as described herein.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of the invention, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof; in particular theinvention encompasses pharmaceutical compositions of one or more of thecompounds of the invention.

The present invention provides pharmaceutical compositions comprisingone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, and one or more prophylactic ortherapeutic agents, said prophylactic or therapeutic agents known to beuseful, or having been or currently being used in the prevention,treatment or amelioration of a disease or disorder associated with orcharacterized by aberrant angiogenesis, a central nervous systemdisorder, a proliferative disorder, an inflammatory disorder, a diseaseor disorder prevented, managed, treated or ameliorated by the inhibitionof phosphodiesterase IV (“PDE4”) activity and/or the inhibition oftubulin polymerization or stability, or one or more symptoms thereof. Inanother embodiment, the pharmaceutical compositions of the invention cancomprise one or more compounds of the invention, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, and one or more vasculartargeting agents.

The present invention also provides a method for inhibiting or reducingtubulin polymerization or stability, said method comprising contacting acell with an effective amount of a compound of the invention.

The present invention also provides a method for inhibiting or reducingtubulin polymerization or stability and PDE4 activity, said methodcomprising contacting a cell with an effective amount of a compound ofthe invention.

The present invention further provides a method for inhibiting PDE4activity, said method comprising contacting a cell with an effectiveamount of a compound of the invention.

The present invention further provides a method for targeting, blockingor destroying the function of tumor vasculature, said method comprisingcontacting a tumor with an effective amount of a compound of theinvention.

The present invention further provides a method for targeting, blockingor destroying the endothelium of tumor vessels, said method comprisingcontacting a tumor with an effective amount of a compound of theinvention.

The present invention further provides a method for occludingpre-existing blood vessels of a tumor, said method comprising contactinga tumor with an effective amount of a compound of the invention.

The present invention further provides a method for killing a tumorcell, said method comprising contacting a tumor cell with an effectiveamount of a compound of the invention.

The present invention further provides a method for causing acutevascular collapse in a tumor cell, said method comprising contacting atumor cell with an effective amount of a compound of the invention.

The present invention further provides a method for blockingangiogenesis through vascular inhibition, said method comprisingcontacting a cell with an effective amount of a compound of theinvention.

The present invention provides a method for inhibiting angiogenesis,said method comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

In another embodiment, the present invention provides a method ofpreventing, treating, managing, or ameliorating a proliferative disorderor an inflammatory disorder or one or more symptoms thereof, said methodcomprising administering a prophylactically or therapeutically effectiveamount of a compound of the invention, alone or in combination with aprophylactically or therapeutically effective amount of one or moretherapies, other than a compound the invention, used or known to beeffective in preventing, treating, managing or ameliorating aproliferative disorder or an inflammatory disorder or one or moresymptoms thereof.

In another embodiment, the present invention provides a method ofpreventing, treating, managing, or ameliorating a central nervous systemdisorder or one or more symptoms thereof, said method comprisingadministering a prophylactically or therapeutically effective amount ofa compound of the invention, alone or in combination with aprophylactically or therapeutically effective amount of one or moretherapies, other than a compound the invention, used or known to beeffective in preventing, treating, managing or ameliorating a centralnervous system disorder or one or more symptoms thereof.

In a specific embodiment, the present invention provides a method ofpreventing, treating, managing, or ameliorating cancer resistant to atubulin binding agent (e.g., Colchicine, Taxol or Vinca Alkaloids) orone or more symptoms thereof, said method comprising administering aprophylactically or therapeutically effective amount of compound of theinvention, alone or in combination with a prophylactically ortherapeutically effective amount of one or more therapies (e.g.,Colchicine, Taxol or Vinca Alkaloids), other than a compound theinvention, used or known to be effective in preventing, treating,managing or ameliorating a proliferative disorder or an inflammatorydisorder or one or more symptoms thereof.

3.1 Terminology and Abbreviations

-   -   As used herein, the term “alkoxy” refers to a compound having        the formula —O-alkyl, —O-lower alkyl, —O-cycloalkyl, —O-lower        alkyl-cycloalkyl, —O-benzyl, —O-lower alkyl-benzyl, wherein        alkyl, lower alkyl and cycloalkyl are as defined below.        Representative —O-lower alkyl groups include, but are not        limited to, —O-methyl, —O-ethyl, —O-n-propyl, —O-n-butyl,        —O-n-pentyl, —O-n-hexyl, —O-n-heptyl, —O-n-octyl, —O-isopropyl,        —O-sec-butyl, —O-isobutyl, —O-tert-butyl, —O-isopentyl,        —O-2-methylbutyl, —O-2-methylpentyl, —O-3-methylpentyl,        —O-2,2-dimethylbutyl, —O-2,3-dimethylbutyl,        —O-2,2-dimethylpentyl, —O-2,3-dimethylpentyl,        —O-3,3-dimethylpentyl, —O-2,3,4-trimethylpentyl,        —O-3-methylhexyl, —O-2,2-dimethylhexyl, —O-2,4-dimethylhexyl,        —O-2,5-dimethylhexyl, —O-3,5-dimethylhexyl,        —O-2,4-dimethylpentyl, —O-2-methylheptyl, —O-3-methylheptyl,        —O-vinyl, —O-allyl, —O-1-butenyl, —O-2-butenyl, —O-isobutylenyl,        —O-1-pentenyl, —O-2-pentenyl, —O-3-methyl-1-butenyl,        —O-2-methyl-2-butenyl, —O-2,3-dimethyl-2-butenyl, —O-1-hexyl,        —O-2-hexyl, —O-3-hexyl, —O—acetylenyl, —O-propynyl,        —O-1-butynyl, —O-2-butynyl, —O-1-pentynyl, —O-2-pentynyl and        —O-3-methyl-1-butynyl. Representative —O-cycloalkyl groups        include, but are not limited to, —O-cyclopropyl, —O-cyclobutyl,        —O-cyclopentyl, —O-cyclohexyl, —O-cycloheptyl, —O-cyclooctyl,        —O-cyclononyl and —O-cyclodecyl. Representative —O-lower        alkyl-cycloalkyl groups include, but are not limited to,        —O—CH₂-cyclopropyl, —O—CH₂-cyclobutyl, —O—CH₂-cyclopentyl,        —O—CH₂-cyclohexyl, —O—CH₂-cycloheptyl, —O—CH₂-cyclooctyl,        —O—CH₂-cyclononyl, —O—CH₂-cyclodecyl, —O—(CH₂)₂-cyclopropyl,        —O—(CH₂)₂-cyclobutyl, —O—(CH₂)₂-cyclopentyl,        —O—(CH₂)₂-cyclohexyl, —O—(CH₂)₂-cycloheptyl,        —O—(CH₂)₂-cyclooctyl, —O—(CH₂)₂-cyclononyl and        —O—(CH₂)₂-cyclodecyl.

As used herein, the term “alkyl” refers to a straight chain or branched,saturated or unsaturated hydrocarbon having from 1 to 20 carbon atoms.Representative straight-chain alkyl groups include, but are not limitedto, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl,-n-heptyl, -n-octyl, -n-nonyl, -n-decyl, -n-undecyl, -n-dodecyl,-n-tridecyl, -n-tetradecyl, -n-pentadecyl and the like; while branchedalkyl groups include, but are not limited to, -isopropyl, -sec-butyl,-isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 2-methylpentyl,3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl,2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl,2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl,2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl; unsaturated alkylsinclude, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl,3-hexyl,-acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl,-2-pentynyl, -3-methyl-1 butynyl, -1-hexynyl, -2-hexynyl, -1-heptynyl,-2-heptynyl, -1-octynyl, -2-octynyl, -1-nonynyl, -2-nonynyl, -1-decynyl,-2-decynyl.

As used herein, the term “alkenyl” means a straight chain or branchednon-cyclic hydrocarbon having from 2 to 10 carbon atoms and including atleast one carbon-carbon double bond. Representative straight chain andbranched alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like.

As used herein, the term “alkynyl” means a straight chain or branchednon-cyclic hydrocarbon having from 2 to 10 carbon atoms and including atlease one carbon-carbon triple bond. Representative straight chain andbranched —(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl, and the like. An alkynylgroup can be unsubstituted or substituted.

As used herein, the terms “antibody” and “antibodies” refer tomonoclonal antibodies, multispecific antibodies, human antibodies,humanized antibodies, camelised antibodies, chimeric antibodies, singledomain antibodies, single chain Fvs (scFv), single chain antibodies, Fabfragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), andanti-idiotopic (anti-Id) antibodies (including, e.g., anti-Id antibodiesto antibodies of the invention), and epitope-binding fragments of any ofthe above. In particular, antibodies include immunoglobulin molecules,e.g., molecules that contain an antigen binding site. Immunoglobulinmolecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY),class (e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgA₁ and IgA₂) or subclass.

As used herein, the term “aryl” refers to a carbocyclic aromatic group.Examples of aryl groups include, but are not limited to, phenyl, benzyl,naphthyl and anthracenyl.

As used herein, the term “cycloalkyl” refers to a 3-, 4-, 5-, 6-, 7- or8-membered saturated or unsaturated non-aromatic carbocyclic ring.Representative C₃-C₈ cycloalkyl groups include, but are not limited to,-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl,-cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl,-1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and-cyclooctadienyl. The term “cycloalkyl” also includes -loweralkyl-cycloalkyl, wherein lower alkyl and cycloalkyl are as definedherein. Examples of -lower alkyl-cycloalkyl groups include, but are notlimited to, —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,—CH₂-cyclopentadienyl, —CH₂-cyclohexyl, —CH₂-cycloheptyl and—CH₂-cyclooctyl.

As used herein, the terms “compound” and “compound of the invention,”are used interchangeably to refer to any compound, includingpharmaceutically acceptable salts, hydrates or solvates thereof,disclosed herein specifically or generically. In one embodiment, thecompounds of the invention are compounds of formulas I-IX and those ofTable 1, and pharmaceutically acceptable salts, hydrates or solvatesthereof. In another embodiment, the compounds of the invention alsoinclude those set forth in PCT International Publication No. WO98/06692, published Feb. 19, 1998 (see, e.g., formula I at page 6, line6 to page 7, line 11 and Examples 1-30) and U.S. Pat. No. 5,929,117,issued Jul. 22, 1999 (see, e.g., formula I at column 4, line 45 tocolumn 5, line 37 and Examples 1-34), each of which is incorporated byreference herein in its entirety. In another embodiment, the compoundsof the invention also include componds of formula X, andpharmaceutically acceptable salts, solvates and hydrates thereof.

As used herein, the terms “disorder” and “disease” are usedinterchangeably to refer to a condition in a subject. Certain conditionsmay be characterized as more than one disorder. For example, certainconditions may be characterized as both non-cancerous proliferativedisorders and inflammatory disorders. In one embodiment, a proliferativedisorder is cancer.

As used herein, the term “effective amount” refers to the amount of acompound of the invention which is sufficient to reduce or amelioratethe severity or duration of a disorder (e.g., a disorder characterizedby aberrant angiogenesis, a central nervous system disorder, aproliferative disorder or a disorder characterized by inflammation(i.e., an inflammatory disorder)) or one or more symptoms thereof,prevent the advancement of a disorder (e.g., a disorder characterized byaberrant angiogenesis, a proliferative disorder or an inflammatorydisorder), cause regression of a disorder (e.g., a proliferativedisorder or an inflammatory disorder), prevent the recurrence,development, or onset of one or more symptoms associated with a disorder(e.g., a disorder characterized by aberrant angiogenesis, aproliferative disorder or an inflammatory disorder), or enhance orimprove the prophylactic or therapeutic effect(s) of another therapy. Ina specific embodiment, with respect to the treatment of cancer, aneffective amount refers to the amount of a compound of the inventionthat inhibits or reduces the proliferation of cancerous cells, inhibitsor reduces the spread of tumor cells (metastasis), inhibits or reducesthe onset, development or progression of one or more symptoms associatedwith cancer, reduces the size of a tumor or kills a tumor cell. In oneembodiment, a therapeutically effective amount of a compound of theinvention is that amount which attacks the tumor vascular system andshuts off the supply of blood and/or oxygen to the tumor. Preferably, atherapeutically effective of a compound of the invention inhibits orreduces the proliferation of cancerous cells or the size of a tumor byat least 5%, preferably at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, or atleast 99%, relative to a control or placebo such as phosphate bufferedsaline (“PBS”). In another embodiment, with respect to inflammation, aneffective amount refers to the amount of a compound of the inventionthat reduces the inflammation of a joint, organ or tissue. Preferably,an effective of a compound of the invention reduces the inflammation ofa joint, organ or tissue by at least 5%, preferably at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99%, relative to a control orplacebo such as phosphate buffered saline. In another embodiment, withrespect to the treatment of psoriasis, an effective amount preferablyrefers to the amount of a compound of the invention that reduces ahuman's Psoriasis Area and Severity Index (PASI) score by at least 20%,at least 35%, at least 30%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, or at least 85%. In an alternative embodiment, with respectto the treatment of psoriasis, an effective amount preferably refers tothe amount of a compound of the invention that improves a human's globalassessment score by at least 25%, at least 35%, at least 30%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, or at least 95%. Examples of therapeutically effective amounts ofcompounds of the invention are provided in Section 4.4.5 infra.

As used herein, the term “halogen” means —F, —Cl, —Br or —I.

As used herein, the term “heterocycle” refers to an aromatic ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. Representative examples of a heterocycle include, but arenot limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl,coumarinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl, thiophenyl, furanyl,thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl,pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl,(1,4)-dioxane, (1,3)-dioxolane, 4,5-dihydro-1H-imidazolyl andtetrazolyl. Heterocycles can be substituted or unsubstituted.Heterocycles can also be bonded at any ring atom (i.e., at any carbonatom or heteroatom of the heterocyclic ring).

As used herein, the term “in combination” refers to the use of more thanone therapies (e.g., one or more prophylactic and/or therapeuticagents). The use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disorder (e.g., a disordercharacterized by aberrant angiogenesis, a proliferative disorder or aninflammatory disorder). A first therapy (e.g., a prophylactic ortherapeutic agent such as a compound of the invention) can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapy (e.g., aprophylactic or therapeutic agent such as an anti-inflammatory agent oranti-angiogenic agent) to a subject with a disorder (e.g., a disordercharacterized by aberrant angiogenesis, a proliferative disorder or aninflammatory disorder).

As used herein, the term “isolated” in the context of a compound suchas, e.g., a compound of the invention, refers to a compound that issubstantially free of chemical precursors, other chemicals whenchemically synthesized or other isomers. In a specific embodiment, thecompound is 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% free of other,different compounds (e.g., other isomers). Preferably, compounds of theinvention are isolated.

As used herein, the term “lower alkyl” refers to a straight chain orbranched, saturated or unsaturated hydrocarbon having from 1 to 8 carbonatoms. Representative straight-chain lower alkyl groups include, but arenot limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl,-n-hexyl, -n-heptyl and -n-octyl; while branched lower alkyl groupsinclude, but are not limited to, -isopropyl, -sec-butyl, -isobutyl,-tert-butyl, -isopentyl, 2-methylbutyl, 2-methylpentyl, 3-methylpentyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl,3-methylhexyl, 2,2-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,3,5-dimethylhexyl, 2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl,unsaturated C₁-C₈ alkyls include, but are not limited to, -vinyl,-allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl,-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,1-hexyl, 2-hexyl, 3-hexyl,-acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1 butynyl.

As used herein, the term “lower hydroxyalkyl” refers to a lower alkylgroup as described herein substituted with one or more hydroxy groups.Representative lower hydroxyalkyl groups include, but are not limitedto, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —(CH₂)₄OH, —(CH₂)₅OH, —CH(OH)CH₃,—CH(OH)CH₂CH₃, —CH(OH)(CH₂)₂CH₃, —CH₂CH(OH)CH₃, —CH₂CH(OH)CH₂CH₃, andthe like.

When the groups described herein are said to be “substituted orunsubstituted,” when substituted, they may be substituted with anydesired substituent or substituents that do not adversely affect thedesired activity of the compound. Examples of preferred substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (e.g., chloro, iodo, bromo, or fluoro); C₁₋₆ alkyl;C₂₋₆ alkenyl; C₂₋₆ alkynyl; hydroxyl; C₁₋₆ alkoxyl; amino; nitro; thiol;thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl;thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; acetyl;acetoxy; carbamoyl; oxygen (═O); haloalkyl (e.g., trifluoromethyl);susbtituted aminoacyl and aminoalkyl; carbocyclic cycloalkyl, which maybe monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, whichmay be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic orheterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino(primary, secondary, or tertiary); o-lower alkyl; o-aryl, aryl;aryl-lower alkyl; CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂; SO₂NH₂; OCHF₂; CF₃;OCF₃; and such moieties may also be optionally substituted by afused-ring structure or bridge, for example —OCH₂O— or —O-loweralkyl-O—. These substituents may optionally be further substituted witha substituent selected from such groups. In one embodiment, when a loweralkyl group (e.g., methylene) is substituted, it is substituted with theside chain of a naturally occurring amino acid.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers, mixtures ofdiastereomers or enantiomerically or optically pure compounds. Thisinvention encompasses the use of stereomerically pure forms of suchcompounds, as well as the use of mixtures of those forms. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular compound of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind., 1972).

It should also be noted the compounds of the invention include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the compounds of the invention areisolated as either the E or Z isomer. In other embodiments, thecompounds of the invention are a mixture of the E and Z isomers.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound or onegeometric isomer (e.g., about a double bond) that is substantially freeof the other geometric isomer. For example, a stereomerically purecompound of the invention having one chiral center, or a compositionthereof, will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound of the invention having twochiral centers, or a composition thereof, will be substantially free ofother diastereomers of the compound. A stereomerically pure compound ofthe invention having a double bond capable of E/Z isomerism, or acomposition thereof, will be substantially free of one of the E/Zisomers. A typical stereomerically pure compound comprises greater thanabout 80% by weight of one stereoisomer or E/Z isomer of the compoundand less than about 20% by weight of other stereoisomers or E/Z isomerof the compound, more preferably greater than about 90% by weight of onestereoisomer or E/Z isomer of the compound and less than about 10% byweight of the other stereoisomers or E/Z isomer of the compound, evenmore preferably greater than about 95% by weight of one stereoisomer orE/Z isomer of the compound and less than about 5% by weight of the otherstereoisomers or E/Z isomer of the compound, and most preferably greaterthan about 97% by weight of one stereoisomer or E/Z isomer of thecompound and less than about 3% by weight of the other stereoisomers orE/Z isomer of the compound. As used herein and unless otherwiseindicated, the term “stereomerically enriched” means a compound of theinvention, or a composition thereof, that comprises greater than about60% by weight of one stereoisomer or E/Z isomer of a compound of theinvention, preferably greater than about 70% by weight, more preferablygreater than about 80% by weight of one stereoisomer or E/Z isomer of acompound of the invention. As used herein and unless otherwiseindicated, the term “enantiomerically pure” means a stereomerically purecompound of the invention having one chiral center, or a compositionthereof. Similarly, the term “stereomerically enriched” means astereomerically enriched compound of the invention having one chiralcenter, or a composition thereof.

It should be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), which does not result in a cure ofthe disease. In certain embodiments, a subject is administered one ormore therapies (e.g., one or more prophylactic or therapeutic agents) to“manage” a disease or a symptom thereof so as to prevent the progressionor worsening of the disease or symptom thereof.

As used herein, the terms “non-responsive” and “refractory” describepatients treated with a currently available therapy (e.g., aprophylactic or therapeutic agent) for a disorder (e.g., a disordercharacterized by aberrant angiogenesis, a proliferative disorder or aninflammatory disorder), which is not clinically adequate to relieve oneor more symptoms associated with such disorder. Typically, such patientssuffer from severe, persistently active disease and require additionaltherapy to ameliorate the symptoms associated with their disorder (e.g.,a disorder characterized by aberrant angiogenesis, a proliferativedisorder or an inflammatory disorder).

As used herein, the phrase “pharmaceutically acceptable salt” refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Preferred salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counterion.The counterion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounterion.

As used herein, the term “pharmaceutically acceptable solvate” refers toan association of one or more solvent molecules and a compound of theinvention. Examples of solvents that form pharmaceutically acceptablesolvates include, but are not limited to, water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the term “pharmaceutically acceptable hydrate” refers toa compound of the invention, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, the terms “prevent,” “preventing” and “prevention” referto the prevention of the recurrence, onset, or development of a disorderor one or more symptoms of a disorder in a subject resulting from theadministration of a therapy (e.g., a prophylactic or therapeutic agent),or the administration of a combination of therapies (e.g., a combinationof prophylactic or therapeutic agents).

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a therapy (e.g., prophylactic agent) which is sufficientto result in the prevention of the development, recurrence or onset of adisorder or one or more symptoms associated with a disorder (e.g., adisorder characterized by aberrant angiogenesis, a proliferativedisorder or an inflammatory disorder), or to enhance or improve theprophylactic effect(s) of another therapy (e.g., another prophylacticagent). Examples of prophylactically effective amounts of compounds areprovided in Section 4.4.5 infra.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapy (e.g., a prophylactic or therapeuticagent). Side effects are always unwanted, but unwanted side effects arenot necessarily adverse. An adverse effect from a therapy (e.g.,prophylactic or therapeutic agent) might be harmful or uncomfortable orrisky. Side effects include, but are not limited to fever, chills,lethargy, gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the terms “subject” and “patient” are usedinterchangeably herein. The terms “subject” and “subjects” refer to ananimal, preferably a mammal including a non-primate (e.g., a cow, pig,horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as acynomolgous monkey, a chimpanzee and a human), and more preferably ahuman. In one embodiment, the subject is refractory or non-responsive tocurrent treatments for a disorder (e.g., a disorder characterized byaberrant angiogenesis, a proliferative disorder or an inflammatorydisorder). In another embodiment, the subject is a farm animal (e.g., ahorse, a cow, or a pig) or a pet (e.g., a dog or a cat). In anotherembodiment, the subject is not an immunocompromised or immunosuppressedmammal, preferably a human (e.g., an HIV patient). In anotherembodiment, the subject is not a mammal, preferably a human, with alymphocyte count under approximately 500 cells/mm³. In a preferredembodiment, the subject is a human.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent) which has been or is currently being used to prevent,manage or treat a disorder (e.g., a disorder characterized by aberrantangiogenesis, a proliferative disorder, an inflammatory disorder or anautoimmune disorder), which is more effective than the additive effectsof the therapies. A synergistic effect of a combination of therapies(e.g., a combination of prophylactic or therapeutic agents) permits theuse of lower dosages of one or more of the therapies and/or lessfrequent administration of said therapies to a subject with a disorder(e.g., a disorder characterized by aberrant angiogenesis, aproliferative disorder or an inflammatory disorder). The ability toutilize lower dosages of a therapy (e.g., a prophylactic or therapeuticagent) and/or to administer said therapy less frequently reduces thetoxicity associated with the administration of said therapy to a subjectwithout reducing the efficacy of said therapy in the prevention,management or treatment of a disorder (e.g., a disorder characterized byaberrant angiogenesis, a proliferative disorder or an inflammatorydisorder). In addition, a synergistic effect can result in improvedefficacy of agents in the prevention, management or treatment of adisorder (e.g., a disorder characterized by aberrant angiogenesis, aproliferative disorder or an inflammatory disorder). A synergisticeffect of a combination of therapies (e.g., a combination ofprophylactic or therapeutic agents) may avoid or reduce adverse orunwanted side effects associated with the use of either therapy alone.In one embodiment, the term synergistic refers to the biological effectof a single compound of the invention on a tumor or tumor cell. Withoutbeing limited by theory, it is thought that because the compounds of theinvention have both vascular targeting activity, which is particularlyeffective against central tumor cells, and anti-angioenic activity,which is particularly effective against peripheral tumor cells, thecompounds of the invention are particularly useful in eradicating themajority of a tumor and, in one embodiment, completely eradicating atumor. Accordingly, the compounds of the invention are particularlyactive against tumors due to the synergistic effects of their dualactivity as both vascular targeting agents and anti-angiogenic agents.

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disorder (e.g., a disorder characterized by aberrantangiogenesis, a proliferative disorder or an inflammatory disorder), orthe amelioration of one or more symptoms thereof resulting from theadministration of one or more therapies (e.g., one or more therapeuticagents such as a compound of the invention). In specific embodiments,such terms refer to the inhibition or reduction in the proliferation ofcancerous cells, the inhibition or reduction in the spread of tumorcells (metastasis), the inhibition or reduction in the onset,development or progression of one or more symptoms associated withcancer, the reduction in the size of a tumor, or the improvement in apatient's ECOG or Kamofsky score. In other embodiments, such terms referto a reduction in the swelling of one or more joints, organs or tissues,or a reduction in the pain associated with an inflammatory disorder. Inyet other embodiments, such terms refer to a reduction a human's PASIscore or an improvement in a human's global assessment score.

As used herein, the terms “tubulin binder,” “tubulin binding agent” orvariants thereof refer to any cytostatic or cytotoxic agent that canbind to tubulin, an α,β-tubulin dimer or to an intact microtubule in acell. In one embodiment, the tubulin binder or tubulin binding agentinhibits tubulin polymerization or stability. In another embodiment, thetubulin binder or tubulin binding agent is a tubulin destabilizer.

As used herein, the terms “inhibit tubulin polymerization or stability”or “inhibition of tubulin polymerization or stability” refer to anyalteration in the structure of tubulin dimers, any hinderance of theassembly of tubulin dimers into microtubules or any destabilization oftubulin dimers.

The following abbreviations are used herein and have the indicateddefinitions: Dess-Martin Periodinane is1,1,1-triacetox-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, DMF isN,N-dimethylformamide, DMSO is dimethylsulfoxide, EtOAc is ethylacetate, HPLC is high performance liquid chromatography, HUVEC is humanumbilical vein endothelial cell, KHMDS is potassiumhexamethyldisilazide, LHMDS is lithium hexamethyldisilazide, PBMC isperipheral blood mononuclear cells, PCC is pyridinium chlorochromate,PDC is pyridinium dichromate, Ph is phenyl, THF is tetrahydrofuran, TLCis thin-layer chromatography and TPAP is tetra-n-propylammoniumperruthenate.

4 DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds and uses of said compounds. Thepresent invention encompasses the use of compounds of the invention toinhibit tubulin polymerization and/or tubulin stability and/or inhibitmitosis. The present invention also encompasses the use of the compoundsof the invention to inhibit angiogenesis. The present invention alsoencompasses the use of the compounds of the invention to inhibit theactivity of PDE4. The present invention also encompasses the use of thecompounds of the invention as vascular targeting agents.

The present invention encompasses treatment protocols that providebetter prophylactic or therapeutic profiles than current single agenttherapies or combination therapies for various disorders (e.g.,disorders characterized by aberrant angiogenesis, proliferativedisorders and inflammatory disorders), or one or more symptoms thereof.In particular, the invention provides prophylactic and therapeuticprotocols for the prevention, treatment, management, or amelioration ofproliferative disorders (e.g., cancer), macular degeneration orinflammatory diseases, or one or more symptoms thereof, comprisingadministering to a subject a prophylactically or therapeuticallyeffective amount of one or more of the compounds of the invention aloneor in combination with a prophylactically or therapeutically effectiveamount of at least one other prophylactic or therapeutic agent otherthan a compound of the invention.

4.1 The Compounds of the Invention

The present invention encompasses compounds having formulas I-IX andthose set forth in Table 1, below.

In one embodiment, the invention provides methods for treating,preventing or managing a disease or disorder described herein comprisingadministering to a patient in need thereof a compound having theformula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower            alkyl, —C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl;        -   R₄ is —H, —NO₂, cyano, substituted or unsubstituted lower            alkyl, substituted or unsubstituted alkoxy, halogen, —OH,            —C(O)(R₁₀)₂, —COOH, —NH₂, —OC(O)—N(R₁₀)₂;        -   R₅ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted alkoxy, or substituted or unsubstituted            alkenyl;        -   X is substituted or unsubstituted phenyl, substituted or            unsubstituted pyridine, substituted or unsubstituted            pyrrolidine, substituted or unsubstituted imidizole,            substituted or unsubstituted naphthalene, substituted or            unsubstituted thiophene, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₉ is independently —H or substituted or            unsubstituted lower alkyl; and        -   each occurrence of R₁₀ is independently —H or substituted or            unsubstituted lower alkyl.

In one embodiment, compounds of formula I are those wherein R₄ and R₅are alkoxy (e.g., methoxy).

In another embodiment, compounds of formula I are those wherein X issubstituted or unsubstituted phenyl.

In another embodiment, the compound of formula I is the E isomer.

In another embodiment, the compound of formula I is the Z isomer.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁ and R₂ are independently —H, —CN, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkenyl, substituted or unsubstituted alkynyl, —COOH,            —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R₉)₂,            substituted or unsubstituted aryl, or substituted or            unsubstituted heterocycle;        -   each occurrence of R_(a), R_(b), R_(c) and R_(d) is            independently —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀, —N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀,            —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,            —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,            —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;        -   R₃ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂, or R₃ with either R_(a) or with R₄,            together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;        -   R₄ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀—NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₅ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₆ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₇ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₈ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) or with R₇,            together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate; and        -   each occurrence of R₁₆ and R₁₇ is independently —H or            halogen.

In a further embodiment, the invention provides compounds of formula IIwherein R₃, R₅, R₆ and R₈ are other than —H. In particular, thisembodiment encompasses 3,3′-bis-3,5-disubstituted phenyl compounds offormula II. This embodiment further encompasses compounds of formula IIwherein:

-   -   R₁, R₂, R₄, R₇, R₉₉, R₁, R₁₆, R₁₇, R_(a), R_(b), R_(c), and        R_(d) are as defined above for formula II;    -   R₃ is substituted or unsubstituted lower alkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocycle,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂,        —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃ with R_(a),        together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;    -   R₅ is substituted or unsubstituted lower alkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocycle,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂,        —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;    -   R₆ is substituted or unsubstituted lower alkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heterocycle,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂,        —N(R₉)₂, —OC(O)—R₁₀—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; and

R₈ is substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂₅—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with R_(c), togetherform —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—.

In a further embodiment, the invention provides compounds of formula IIwherein if one of R₃ or R₅ is H, then the other is not lower alkyl oralkoxy and if one of R₆ or R₈ is H, then the other is not lower alkyl oralkoxy. In particular, this embodiment encompasses compounds of formulaII wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₆, R₁₇, R_(a), R_(b),        R_(c) and R_(d) are as described above for formula II,    -   with the proviso that if one of R₃ or R₅ is H, then the other is        not substituted or unsubstituted lower alkyl or substituted or        unsubstituted alkoxy and if one of R₆ or R₈ is H, then the other        is not substituted or unsubstituted lower alkyl or substituted        or unsubstituted alkoxy.

In a further embodiment, the invention provides compounds of formula IIwherein one of R₄ and R₇ are other than —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂or —OH. In particular, this embodiment encompasses 3,3-bis-4-substitutedphenyl compounds of formula II. This embodiment further encompassescompounds of formula II wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₀, R₁₆, R₁₇, R_(a), R_(b),        R_(c), and R_(d) are as defined above for formula II;    -   wherein one of R₄ and R₇ is —OPO(OH)₂, —N(R₉)₂,        —OC(O)—R₁₀—N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,        —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,        —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;        and    -   R₉ is substituted or unsubstituted lower alkyl, or substituted        or unsubstituted cycloalkyl.

In a further embodiment, the invention provides compounds of formula IIwherein at least one of R₃, R₄, R₅, R₆, R₇ or R₈ is other than —H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, amino. In particular, this embodimentencompasses 3-(3-, 4- or 5-)-substituted phenyl compounds of formula II.This embodiment further encompasses compounds of formula II wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₀, R₁₆, R₁₇, R_(a), R_(b),        R_(c), and R_(d) are as defined above for formula II;    -   R₉ is substituted or unsubstituted lower alkyl, or substituted        or unsubstituted cycloalkyl;    -   wherein at least one of R₃, R₄, R₅, R₆, R₇, R₈, R_(a), R_(b),        R_(c) or R_(d) is —O—(C₄-C₁₀ alkyl)-cycloalkyl, —OPO(OH)₂,        —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —N(R₉)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂. This embodiment also        encompasses compounds of formula II wherein at least one of R₃,        R₄, R₅, R₆, R₇, R_(b), R_(a), R_(b), R_(b) or R_(d) is        —OPO(OH)₂, —OC(O)—R₁₀—N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,        —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,        —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂.

In a further embodiment, the invention provides compounds of formula IIwherein at least one of R_(a) and R_(b) and at least one of R_(c) andR_(d) is substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂. In particular, thisembodiment encompasses 3-(2- or 6-)-substituted-3′-(2- or6-)-substituted phenyl compounds of formula II. This embodiment furtherencompasses compounds of formula II wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈) R₉, R₁₀, R₁₆, R₁₇, R_(a), R_(b),        R_(c), and R_(d) are as defined above for formula II, and    -   wherein at least one R_(a) and R_(b) and at least one of R_(d)        and R_(d) is other than —H.

In a further embodiment, the invention provides compounds of formula IIwherein either R₃ and one of R_(a) and R₄, together form —O—(C(R₁₆R₁₇))₂—O— or R₈ and one of R_(d) and R₇, together form—O—(C(R₁₆R₁₇))₂—O—.

In a further embodiment, the invention provides compounds of formula IIwherein R₁ and R₂ are both other than —H. In particular, this embodimentencompasses compounds of formula II wherein:

-   -   R₁ and R₂ are independently —CN, substituted or unsubstituted        lower alkyl, substituted or unsubstituted alkynyl, —COOH,        —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted        or unsubstituted aryl, or substituted or unsubstituted        heterocycle; and    -   R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₆, R₁₇, R_(a), R_(b), R_(c),        and R_(d) are as defined above for formula II.

The following embodiments relate to the compounds of formula II and,where applicable, to the further embodiments of the compounds of formulaII described above.

In one embodiment, the compounds of formula II are those wherein alloccurrences of R_(a), R_(b), R_(d) and R_(d) are —H.

In another embodiment, the compounds of formula II are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is other than —H.

In another embodiment, the compounds of formula II are those wherein atleast one occurrence of R_(a) and R_(b) and at least one occurrence ofR_(d) and R_(d) is other than —H.

In another embodiment, the compounds of formula II are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is alkoxy.

In another embodiment, the compounds of formula II are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is methoxy.

In another embodiment, the compounds of formula II are those wherein R₁is —H and R₂ is —CN.

In another embodiment, the compounds of formula II are those wherein R₁is —CN and R₂ is —H.

In another embodiment, the compounds of formula II are those wherein thecompound is the E isomer.

In another embodiment, the compounds of formula II are those wherein thecompound is the Z isomer.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄ and R₅ and at least one of R₆, R₇ and R₈ is otherthan —H.

In another embodiment, the compounds of formula II are those wherein R₃is alkoxy and R₄ is alkoxy.

In another embodiment, the compounds of formula II are those wherein R₃is methoxy and R₄ is methoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄ and R₅ and at least one of R₆, R₇ and R₈ is alkoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄ and R₅ and at least one of R₆, R₇ and R₈ is methoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄ and R₅ and at least one of R₆, R₇ and R₈ is ethoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄, R₅, R₆, R₇ and R₈ is alkoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄, R₅, R₆, R₇ and R₈ is methoxy.

In another embodiment, the compounds of formula II are those wherein atleast one of R₃, R₄, R₅, R₆, R₇ and R₈ is ethoxy.

In another embodiment, the compounds of formula II are those whereineither R₃ and R₅ or R₆ and R₈ are both alkoxy.

In another embodiment, the compounds of formula II are those whereineither R₃ and R₅ or R₆ and R₈ are both methoxy.

In another embodiment, the compounds of formula II are those wherein oneof R₃ and R₅ is methoxy and the other is ethoxy or one of R₆ and R₈ ismethoxy and the other is ethoxy.

In another embodiment, the compounds of formula II are those whereineither R₃, R₄ and R₅ or R₆, R₇ and R₈ are all alkoxy.

In another embodiment, the compounds of formula II are those whereineither R₃, R₄ and R₅ or R₆, R₇ and R₈ are all methoxy.

In another embodiment, the compounds of formula II are those wherein R₃and R₅ are methoxy and one of R₆ and R₈ is methoxy.

In another embodiment, the compounds of formula II are those whereinwhen R₁₀ is substituted lower alkyl (e.g., methylene), R₁₀ issubstituted with the side chain of a natural amino acid. In particular,R₁₀ may be substituted with: —H, —CH₃, —(CH₂)₃NHC(═NH)NH₂, —CH₂C(═O)NH₂,—CH₂C(═O)OH, —CH₂SH, —(CH₂)₂C(═O)NH₂, —(CH₂)₂C(═O)OH, —CH₂-imidazole,—CH(CH₃)(CH₂CH₃), —CH₂CH(CH₃)₂, —(CH₂)₃NH₂, —(CH₂)₂SCH₃, —CH₂-phenyl,—CH₂OH, ═CH(OH)(CH₃), —CH₂-indole, —CH₂-phenol or —CH(CH₃)₂.

In another embodiment, the compounds of formula II are those wherein R₃and R₅ are methoxy, R₇ is methoxy and one of R₆ and R₈ is—NHC(O)—R₁₀—NH₂.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁ and R₂ are independently —H, —CN, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkenyl, substituted or unsubstituted alkynyl, —COOH,            —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R₉)₂,            substituted or unsubstituted aryl, or substituted or            unsubstituted heterocycle;        -   each occurrence of R_(c) and R_(d) is independently —H,            substituted or unsubstituted lower alkyl, substituted or            unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀,            —NH₂;        -   R₃ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀,            —NH₂;        -   R₅ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₆ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₇ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₈ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) or with R₇,            together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate; and        -   each occurrence of R₁₆ and R₁₇ is independently —H or            halogen.

In one embodiment, the compounds of formula III are those wherein R_(c)and R_(d) are —H.

In another embodiment, the compounds of formula III are those wherein atleast one of R_(c) or R_(d) is other than —H.

In another embodiment, the compounds of formula III are those wherein atleast one of R_(c) or R_(d) is -alkoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R_(c) or R_(d) is methoxy.

In another embodiment, the compounds of formula III are those wherein R₁is —H and R₂ is —CN.

In another embodiment, the compounds of formula III are those wherein R₁is —CN and R₂ is —H.

In another embodiment, the compounds of formula III are those whereinthe compound is the E isomer.

In another embodiment, the compounds of formula III are those whereinthe compound is the Z isomer.

In another embodiment, the compounds of formula III are those wherein atleast one of R₆, R₇ and R₈ is other than —H.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃ and R₅ and at least one of R₆, R₇ and R₈ is alkoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃ and R₅ and at least one of R₆, R₇ and R₈ is methoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃ and R₅ and at least one of R₆, R₇ and R₈ is ethoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃, R₅, R₆, R₇ and R₈ is alkoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃, R₅, R₆, R₇ and R₈ is methoxy.

In another embodiment, the compounds of formula III are those wherein atleast one of R₃, R₅, R₆, R₇ and R₈ is ethoxy.

In another embodiment, the compounds of formula III are those wherein R₃and R₅ are both alkoxy.

In another embodiment, the compounds of formula III are those wherein R₃and R₅ are both methoxy.

In another embodiment, the compounds of formula III are those whereinone of R₃ and R₅ is methoxy and the other is alkoxy.

In another embodiment, the compounds of formula III are those wherein R₃and R₅ are methoxy and one of R₆ and R₈ is methoxy.

In another embodiment, the compounds of formula III are those whereinone of R₆ and R₈ is heterocycle or —NHC(O)R₁₀—N(R₉)₂.

In another embodiment, the compounds of formula III are those wherein R₃and R₅ are methoxy, R₇ is methoxy and one of R₆ and R₈ is—NHC(O)—R₁₀—NH₂.

In another embodiment, the compounds of formula III do not include3-(3,4-dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)-acrylonitrile.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁ and R₂ are independently —H, —CN, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkenyl, substituted or unsubstituted alkynyl, —COOH,            —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R₉)₂,            substituted or unsubstituted aryl, or substituted or            unsubstituted heterocycle;        -   each occurrence of R_(c) and R_(d) is independently —H,            substituted or unsubstituted lower alkyl, substituted or            unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₃ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₅)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₄ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,            —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₅ is substituted or unsubstituted lower alkyl, substituted            or unsubstituted aryl, substituted or unsubstituted            heterocycle, substituted or unsubstituted cycloalkyl,            substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,            —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂₅—C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₆ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R o)(N(R₉)₂) or —NHC(O)—R₁₀,            —NH₂;        -   R₇ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀, —N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀,            —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(RF₁₀)₂,            —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,            —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;    -   R₈ is —H, substituted or unsubstituted lower alkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heterocycle,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂,        —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either        R_(c) or with R₇, together form —O—C(R₁₆R₁₇)—O— or        —O—(C(R₁₆R₁₇))₂—O—;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate; and        -   each occurrence of R₁₆ and R₁₇ is independently —H or            halogen.

In one embodiment, the compounds of formula IV are those R_(c) and R_(d)are —H.

In another embodiment, the compounds of formula IV are those wherein atleast one of R_(c) or R_(d) is other than —H.

In another embodiment, the compounds of formula IV are those wherein atleast one of R_(c) or R_(d) is alkoxy.

In another embodiment, the compounds of formula IV are those wherein atleast one of R_(c) or R_(d) is methoxy.

In another embodiment, the compounds of formula IV are those wherein R₁is —H and R₂ is —CN.

In another embodiment, the compounds of formula IV are those wherein R₁is —CN and R₂ is —H.

In another embodiment, the compounds of formula IV are those wherein thecompound is the E isomer.

In another embodiment, the compounds of formula IV are those wherein thecompound is the Z isomer.

In another embodiment, the compounds of formula IV are those wherein atleast one of R₆, R₇ and R₈ is other than —H.

In another embodiment, the compounds of formula IV are those wherein atleast one of R₃, R₄ and R₅ is alkoxy.

In another embodiment, the compounds of formula IV are those wherein atleast one of R₃, R₄ and R₅ is methoxy.

In another embodiment, the compounds of formula IV are those wherein atleast one of R₃, R₄ and R₅ is ethoxy.

In another embodiment, the compounds of formula IV are those wherein R₃,R₅, R₆ and R₈ are alkoxy.

In another embodiment, the compounds of formula IV are those whereineither R₃, R₅, R₆ and R₈ are methoxy.

In another embodiment, the compounds of formula IV are those wherein oneof R₃ and R₅ is methoxy and the other is ethoxy.

In another embodiment, the compounds of formula IV are those wherein R₃and R₅ are methoxy and one of R₆ and R₈ is methoxy.

In another embodiment, the compounds of formula IV are those wherein R₃and R₅ are methoxy, R₇ is methoxy and one of R₆ and R₈ is—NHC(O)—R₁₀—NH₂.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁ and R₂ are independently —H, —CN, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkenyl, substituted or unsubstituted alkynyl, —COOH,            —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R₉)₂,            substituted or unsubstituted aryl, or substituted or            unsubstituted heterocycle;        -   each occurrence of R_(a), R_(b), R_(c) and R_(d) is            independently —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₃ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂, or R₃ with either R_(a) or with R₄,            together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;        -   R₄ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—RWo, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;        -   R₅ is —H, substituted or unsubstituted lower alkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heterocycle, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted alkoxy, halogen,            cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,            —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,            —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,            —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or            —NHC(O)—R₁₀—NH₂;    -   R₆ is —H, substituted or unsubstituted lower alkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heterocycle,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂,        —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,        —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,        —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,        —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate;        -   each occurrence of R₁₆ and R₁₇ is independently —H or            halogen; and        -   n is 1, 2 or 3.

In one embodiment, the compounds of formula V are those wherein alloccurrences of R_(a), R_(b), R_(d) and R_(d) are —H.

In another embodiment, the compounds of formula V are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is other than —H.

In another embodiment, the compounds of formula V are those wherein atleast one occurrence of R_(a) and R_(b) and at least one occurrence ofR_(c) and R_(d) is other than —H.

In another embodiment, the compounds of formula V are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is -alkoxy.

In another embodiment, the compounds of formula V are those wherein atleast one occurrence of R_(a), R_(b), R_(c) or R_(d) is methoxy.

In another embodiment, the compounds of formula V are those wherein R₁is —H and R₂ is —CN.

In another embodiment, the compounds of formula V are those wherein R₁is —CN and R₂ is —H.

In another embodiment, the compounds of formula V are those wherein thecompound is the E isomer.

In another embodiment, the compounds of formula V are those wherein thecompound is the Z isomer.

In another embodiment, the compounds of formula V are those wherein atleast one of R₃, R₄ and R₅ is other than —H and R₆ is other than —H.

In another embodiment, the compounds of formula V are those wherein atleast one of R₃, R₄ and R₅ is alkoxy and R₆ is alkoxy.

In another embodiment, the compounds of formula V are those wherein atleast one of R₃, R₄ and R₅ is methoxy and R₆ is methoxy.

In another embodiment, the compounds of formula V are those wherein atleast one of R₃, R₄ and R₅ is ethoxy and R₆ is ethoxy.

In another embodiment, the compounds of formula V are those wherein R₃,R₅ and R₆ are alkoxy.

In another embodiment, the compounds of formula V are those wherein R₃,R₅ and R₆ are methoxy.

In another embodiment, the compounds of formula V are those wherein oneof R₃ and R₅ is methoxy and the other is ethoxy.

In another embodiment, the compounds of formula V are those wherein R₃,R₄ and R₅ are all alkoxy

In another embodiment, the compounds of formula V are those wherein R₃,R₄ and R₅ are all methoxy.

In another embodiment, the compounds of formula V are those wherein R₃and R₅ are methoxy and R₆ is methoxy.

In another embodiment, the compounds of formula V are those wherein n is2 or 3.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁₁, R₁₂ and R₁₃ are independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl;        -   R₁₄ and R₁₅ are independently —H, O, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heterocycle, substituted            or unsubstituted cycloalkyl, —C(O)—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —C(O)—R₁₀, —S(O)₂—R₁₀, —C(O)NH—R₁₀,            —C(O)N(R₁₀)₂, —C(O)NHSO₂—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)—R₁₀—NH₂, —C(O)—CH(R₁₀)(N(R₉)₂), —C(O)-lower            alkyl-N(R₉)₂ or R₁₄ and R₁₅ and the nitrogen to which they            are attached form a heterocycle;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate;        -   with the proviso that R₁₄ and R₁₅ cannot both be —H.

In one embodiment, the compounds of formula VI are those wherein R₁₁ ismethyl, ethyl, propyl or —CH₂-cyclopropyl.

In another embodiment, the compounds of formula VI are those wherein R₁₂is methyl, difluoromethyl or trifluoromethyl.

In another embodiment, the compounds of formula VI are those wherein R₁₃is methyl.

In another embodiment, the compounds of formula VI are those wherein R₁₄is —H and R₁₅ is —C(O)NH—R₁₀, —C(O)N(R₁₀)₂, —C(O)—CH(R₁₀)(N(R₉)₂),—C(O)-lower alkyl-N(R₉)₂ or —C(O)N(R₁₀)₂.

In another embodiment, the compounds of formula VI are those wherein R₁₄and R₁₅ and the nitrogen to which they are attached form a heterocycle.

In another embodiment, the compounds of formula VI are those whereinR₁₁, R₁₂ and/or R₁₃ are lower alkyl substituted with cycloalkyl and/orhalogen.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁₁, R₁₂ and R₁₃ are independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl;        -   R₁₄ and R₁₅ are independently —H, O, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heterocycle, substituted            or unsubstituted cycloalkyl, —C(O)—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —C(O)—R₁₀, —S(O)₂—R₁₀, —C(O)NH—R₁₀,            —C(O)N(R₁₀)₂, —C(O)NHSO₂—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)—R₁₀—NH₂, —C(O)—CH(R₁₀)(N(R₉)₂), —C(O)-lower            alkyl-N(R₉)₂ or R₁₄ and R₁₅ and the nitrogen to which they            are attached form a heterocycle;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate;        -   with the proviso that R₁₄ and R₁₅ cannot both be —H.

In one embodiment, the compounds of formula VII are those wherein R., ismethyl, ethyl, propyl or —CH₂-cyclopropyl.

In another embodiment, the compounds of formula VII are those whereinR₁₂ is methyl, difluoromethyl or trifluoromethyl.

In another embodiment, the compounds of formula VII are those whereinR₁₃ is methyl.

In another embodiment, the compounds of formula VII are those whereinR₁₄ is —H and R₁₅ is —C(O)NH—R₁₀, —C(O)N(R₁₀)₂, —C(O)—CH(R₁₀)(N(R₉)₂),—C(O)-lower alkyl-N(R₉)₂ or —C(O)N(R₁₀)₂.

In another embodiment, the compounds of formula VII are those whereinR₁₄ and R₁₅ and the nitrogen to which they are attached form aheterocycle.

In another embodiment, the compounds of formula VII are those whereinR₁₁, R₁₂ and/or R₁₃ are lower alkyl substituted with cycloalkyl and/orhalogen.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁₁, R₁₂ and R₁₃ are independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl;        -   R₁₄ and R₁₅ are independently —H, O, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heterocycle, substituted            or unsubstituted cycloalkyl, —C(O)—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —C(O)—R₁₀, —S(O)₂—R₁₀, —C(O)NH—R₁₀,            —C(O)N(R₁₀)₂, —C(O)NHSO₂—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)—R₁₀—NH₂, —C(O)—CH(R₁₀)(N(R₉)₂), —C(O)-lower            alkyl-N(R₉)₂ or R₁₄ and R₁₅ and the nitrogen to which they            are attached form a heterocycle;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate;    -   with the proviso that R₁₄ and R₁₅ cannot both be —H.

In one embodiment, the compounds of formula VIII are those wherein R₁₁is methyl, ethyl, propyl or —CH₂-cyclopropyl.

In another embodiment, the compounds of formula VIII are those whereinR₁₂ is methyl, difluoromethyl or trifluoromethyl.

In another embodiment, the compounds of formula VIII are those whereinR₁₃ is methyl.

In another embodiment, the compounds of formula VIII are those whereinR₁₄ is —H and R₁₅ is —C(O)NH—R₁₀, —C(O)N(RO)₂, —C(O)—CH(R₁₀)(N(R₉)₂),—C(O)-lower alkyl-N(R₉)₂ or —C(O)N(R₁₀)₂.

In another embodiment, the compounds of formula VIII are those whereinR₁₄ and R₁₅ and the nitrogen to which they are attached form aheterocycle.

In another embodiment, the compounds of formula VIII are those whereinR₁₁, R₁₂ and/or R₁₃ are lower alkyl substituted with cycloalkyl and/orhalogen.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   R₁₁, R₁₂ and R₁₃ are independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl;        -   R₁₄ and R₁₅ are independently —H, O, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heterocycle, substituted            or unsubstituted cycloalkyl, —C(O)—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)N(R₁₀)₂, —C(O)—R₁₀, —S(O)₂—R₁₀, —C(O)NH—R₁₀,            —C(O)N(R₁₀)₂, —C(O)NHSO₂—R₁₀, —C(O)—R₁₀—N(R₁₀)₂,            —C(O)—R₁₀—NH₂, —C(O)—CH(R₁₀)(N(R₉)₂), —C(O)-lower            alkyl-N(R₉)₂ or R₁₄ and R₁₅ and the nitrogen to which they            are attached form a heterocycle;        -   each occurrence of R₉ is independently —H, substituted or            unsubstituted lower alkyl, or substituted or unsubstituted            cycloalkyl;        -   each occurrence of R₁₀ is independently substituted or            unsubstituted lower alkyl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted aryl, substituted            or unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen            to which it is attached form a substituted or unsubstituted            heterocycle, or R₁₀ is —H where appropriate;        -   with the proviso the R₁₄ and R₁₅ cannot both be —H.

In one embodiment, the compounds of formula IX are those wherein R₁₁ ismethyl, ethyl, propyl or —CH₂-cyclopropyl.

In another embodiment, the compounds of formula IX are those wherein R₁₂is methyl, difluoromethyl or trifluoromethyl.

In another embodiment, the compounds of formula IX are those wherein R₁₃is methyl.

In another embodiment, the compounds of formula IX are those wherein R₁₄is —H and R₁₅ is —C(O)NH—R₁₀, —C(O)N(R₁₀)₂, —C(O)—CH(R₁₀)(N(R₉)₂),—C(O)-lower alkyl-N(R₉)₂ or —C(O)N(R₁₀)₂.

In another embodiment, the compounds of formula IX are those wherein R₁₄and R₁₅ and the nitrogen to which they are attached form a heterocycle.

In another embodiment, the compounds of formula IX are those wherein R₁,R₁₂ and/or R₁₃ are lower alkyl substituted with cycloalkyl and/orhalogen.

In one embodiment, the invention provides compounds having the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

-   -   wherein:        -   (a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0,            1, 2, or 3, and R₁ is alkyl of one to 10 carbon atoms,            monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of            up to 10 carbon atoms, or benzocyclic alkyl of up to 10            carbon atoms, or        -   (b) X is —CH═ and R₁ is alkylidene of up to 10 carbon atoms,            monocycloalkylidene of up to 10 carbon atoms, or            bicycloalkylidene of up to 10 carbon atoms;        -   R₂ is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy,            carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,            carboxy, hydroxy, amino, lower alkyl, lower            alkylidenemethyl, lower alkoxy, or halo;        -   R₃ is (i) phenyl, unsubstituted or substituted with 1 or            more substituents each selected independently from nitro,            cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy,            carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with            alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy,            amino, amino substituted with an alkyl of 1 to 5 carbon            atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to            10 carbon atoms, alkoxy of up to 10 carbon atoms,            cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl of up            to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon            atoms, phenyl, or methylenedioxy; (ii) pyridine, substituted            pyridine, pyrrolidine, imidizole, naphthalene, or            thiophene; (iii) cycloalkyl of 4-10 carbon atoms,            unsubstituted or substituted with 1 or more substituents            each selected independently from the group consisting of            nitro, cyano, halo, trifluoromethyl, carbethoxy,            carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,            carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10            carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;        -   each of R₄ and R₅ taken individually is hydrogen or R₄ and            R₅ taken together are a carbon-carbon bond;        -   Y is —COZ, —C≡N, or lower alkyl of 1 to 5 carbon atoms;

-   Z is —OH, —NR₆R₆, —R₇, or —OR₇;    -   R₆ is hydrogen or lower alkyl; and

R₇ is alkyl or benzyl.

Illustrative examples of the compounds of the invention include thoseset forth in Table 1, below, and pharmaceutically acceptable salts,solvates or hydrates thereof. It should be noted that the E/Z andcis/trans isomers of these compounds are specifically contemplated.TABLE 1 Comp. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

Compounds of the invention also include those set forth in PCTInternational Publication No. WO 98/06692, published Feb. 19, 1998 (see,e.g., formula I at page 6, line 6 to page 7, line 11 and Examples 1-30)and U.S. Pat. No. 5,929,117, issued Jul. 22, 1999 (see, e.g., formula Iat column 4, line 45 to column 5, line 37 and Examples 1-34), each ofwhich is incorporated by reference herein in its entirety.

In a particular embodiment, the compounds of the invention include:3,3-bis-(3,4-dimethoxyphenyl) acrylonitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile, methyl3,3-bis-(3-ethoxy-4-methoxyphenyl)-propenoate, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)-acrylonitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropene,1-(3-cyclopentoxy-4-methoxyphenyl)-1-phenylpropane,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,3,3-bis-(3,4-dimethoxyphenyl)-propanenitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile,4,4-bis-(3,4-dimethoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-phenylbut-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-cyclopentoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-indan2-yloxy-4-methoxyphenyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one; methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;4-(3-ethoxy-4-methoxyphenyl)-4-(2-furyl)but-3-en-2-one;3-(3-ethoxy-4-methoxyphenyl)-3-(2-furyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)butan-2-one;4,4-bis-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pent-1-en-3-one;1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3,4-dimethoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;3,3-bis-(3,4-dimethoxyphenyl)propanamide;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-phenylacetate;3-phenyl-3-(3′-ethoxy-4-methoxyphenyl)acrylamide;1-(3,4-dimethoxyphenyl)-1-phenylprop-1-ene;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene;3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile;3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropionitirle;3-(3,4-dimethxyphenyl)-3-(3′,5′-dimethoxyphenyl)-acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile;3-(3′-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3,4-dimethoxy-3′-aminobenzophenone;3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3,4-dimethoxy-4′aminobenzophenone;3-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile;3-(4-biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-naphth-2-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-pyridine-4-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-(2-furyl)acrylonitrile;3-(3,4-diethylphenyl)-3-phenylacrylonitrile;3-(3,4-diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;4-(3-ethoxy-4-methoxyphenyl)-4-phenyl-3-butan-2-one;3-(3,4-dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile;2′,6′,3,4-tetramethoxybenzophenone; and pharmaceutically acceptablesalts, solvates and hydrates thereof.

In a particular, the invention encompasses compounds that inhibit orreduce tubulin polymerization and/or stability. In a specificembodiment, the invention encompasses compounds that inhibit or reducetubulin polymerization or stability and inhibit or reduce the expressionone or more activities of tumor necrosis factor-α (TNF-α). In anotherembodiment, the invention encompasses compounds that inhibit or reducetubulin polymerization or stability and inhibit or reduce the expressionof one or more activities of PDE4. In another embodiment, the inventionencompasses compounds of formula I that inhibit or reduce tubulinpolymerization or stability, inhibit or reduce the expression of one ormore activities of TNF-α, and inhibit or reduce the expression of one ormore activities of PDE4. In yet another embodiment, the inventionencompasses compounds that arrest the cell cycle in G₂/M phase.

As discussed above, certain compounds of the invention may contain oneor more chiral atoms. Thus, the invention encompasses all stereoisomers(i.e., geometric isomers) including conformational and configurational(e.g., enantiomers, diastereoisomers, and mixtures thereof). In oneembodiment, the invention includes the racemic or either the R- orS-enantiomers of all the compounds described herein. The enantiomers mayeach be provided in a form substantially free of the other enantiomer(e.g., at least 75% free (w/w), at least 90% free (w/w) or at least 99%free (w/w)) or as mixtures (e.g., racemic mixtures).

The compounds of the invention also contain olefins which, ifasymmetrically substituted, can exist in both the E and Z or cis andtrans configurations. Thus, the invention encompasses both the E and Zand cis and trans olefin isomers of these compounds. For example, acompound whose structure is depicted as:

is understood to encompass both the E and Z olefin isomers having thestructures:

4.1 Methods for Making Compounds of the Invention

Compounds of the invention can be made using conventional organicsyntheses. By way of example and not limitation, a compound of theinvention having the formula I supra may be prepared as outlined inSchemes 1-4.

Scheme 1 shows how compounds of formula I can be made using aFriedel-Crafts acylation process.

A benzoyl chloride compound of formula 44 is coupled with a phenylcompound of formula 45 using a Friedel-Crafts acylation process (March,J. Advanced Organic Chemistry—Reactions, Mechanisms and Structure,4^(th) Ed., John Wiley and Sons, New York, 1992, p. 539-542) to yield anintermediate benzophenone of formula 46. The benzophenone is thenreacted with a phosphorane of formula 47 or a phosphonate of formula 48in the presence of a base, such as lithium hexamethyldisilazide orpotassium hexamethyldisilazide, using Wittig chemistry (March, J.Advanced Organic Chemistry—Reactions, Mechanisms and Structure, 4^(th)Ed., John Wiley and Sons, New York, 1992, p. 956-963) to yield thecorresponding compound I.

In one embodiment, the base used in the Wittig reaction is LHMDS.

In another embodiment, the base used in Wittig reaction is KHMDS.

General Procedure A—Fridel-Crafts Acylation

To a 0.5 to 1.0 M solution of a phenyl compound of formula 45 (about 1eq) in methylene chloride at 0° C. is added aluminum trichloride (about1 eq). To the resulting mixture is added a benzoyl chloride of formula44 (about 1 eq) and the reaction is allowed to warm to room temperature.The reaction mixture is then diluted with methylene chloride, washedusing water (3×), dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a crude residue. The crude residue ispurified using flash column chromatography (hexane/EtOAc) to provide acompound of formula 46.

General Procedure B—Wittig Reaction

To a 0.5 to 1.0 M solution of a phosphorane of formula 47 or aphosphonate of formula 48 (about 1 eq) in THF at 0° C. is added KHMDS(about 1.5 eq). The resulting mixture is allowed to warm to roomtemperature and is then stirred for an additional time of about 15minutes to about 1 hour, after which time am approximately 1.0 Msolution of a benzophenone of formula 46 (about 1.5 eq) in THF is addedand the resulting mixture is heated at reflux for about 4 hours to about36 hours while being monitored using TLC. The reaction is allowed tocool to room temperature and is then concentrated in vacuo to provide acrude residue which is purified using flash column chromatography(hexane/EtOAc) to provide a compound of formula I.

Scheme 2 shows how compounds of Formula I can be prepared using Grignardchemistry.

A bromo- or chlorobenzene of formula 43 is reacted with magnesium tomake the corresponding Grignard reagent which is then reacted with abenzaldehyde of formula 44 to provide a diphenyl hydroxy compound ofFormula 45. Hydroxy compound 45 is then treated with an oxidizing agentto provide an intermediate benzophenone compound of Formula 40 which isreacted with an appropriate phosphorane 47 or phosphonate 48, asdepicted in Scheme 1 herein above, in a Wittig reaction to provide acompound of Formula I.

Suitable oxidizing agents useful in the conversion of a compound offormula 45 to a compound of formula 40 include, but are not limited topyridinium chlorochromate (PCC), pyridinium dichromate (PDC), JonesReagent, Dess-Martin periodinane, MnO₂ and tetra-n-propylperruthenate(TPAP).

In a preferred embodiment the oxidizing agent is PCC.

General Procedure C— Grignard Reaction

To an approximately 0.5M solution of magnesium turnings (about 1.2 eq)in THF is slowly added about one-fourth of the volume of anapproximately 0.5M solution of a bromobenzene compound of formula 43(about 1.2 eq) in THF. The resulting mixture is heated to reflux forabout 30 minutes, then the heat source is removed and the remainder ofthe bromobenzene compound of formula 43 is added dropwise. The resultingmixture is heated to reflux for about 5 hours to about 24 hours, thenallowed to cool to room temperature and stirred for about 18 hours atroom temperature. The resulting solution is then added to anapproximately 0.5 M solution of a benzaldehyde compound of formula 44 inTHF at about 0° C. at a rate such that the reaction temperature does notexceed 15° C. during the addition. After the addition is complete, theresulting reaction is allowed to stir for about 12 hours to about 24hours at room temperature and is then cooled to about 0° C. and quenchedwith saturated aqueous ammonium chloride. The resulting mixture isextracted using EtOAc (3×) and the combined organic extracts are washedwith water (3×), brine, dried over magnesium sulfate and concentrated invacuo to provide a crude residue which is purified using flash columnchromatography (hexane/EtOAc eluent) to provide a hydroxy compound offormula 45.

General Procedure D—Oxidation of a Hydroxy Compound of Formula 45

To an approximately 0.5M solution of a hydroxy compound of formula 45(about 1 eq) in methylene chloride is added pyridinium chlorochromate(about 1.5 eq) and celite (about 100 mg per 1 mmol of a hydroxy compoundof formula 45) and the resulting mixture is allowed to stir for about 6hours to about 24 hours. The reaction mixture is filtered, the resultingfiltercake is washed using methylene chloride and the filtrate andwashings are combined and concentrated in vacuo to afford a cruderesidue which is purified using flash column chromatography to provide abenzophenone compound of formula 40 which can be transformed to acompound of formula I using General Procedure B as described hereinabove.

Scheme 3 shows the synthesis of compounds of formula I via the palladiumcatalyzed coupling of a styrene and a bromobenzene.

General Procedure E—Palladium-catalyzed Coupling of a Styrene and aBromobenzene

To a suspension of a styrene compound of formula 52 (about 1 eq), abromobenzene compound of formula 53 (about 1.5 eq), sodium acetate(about 1.7 eq) and tetra-n-butyl ammonium bromide (about 1.1 eq) in DMFis added an approximately 0.5M suspension of Pd(OAc)₄ (about 0.03 eq) inDMF. The resulting mixture is heated to 60° C. and allowed to stir atthis temperature for about 6 hours to about 18 hours and is then cooledto room temperature and poured into a mixture of water:EtOAc (3:1). Theorganic phase was collected and the aqueous phase was washed using EtOAc(3×). The combined organic extracts were washed sequentially with waterand brine, then dried over magnesium sulfate, filtered and concentratedin vacuo to provide a crude residue which was purified using flashcolumn chromatography to provide a compound of formula I.

Scheme 4 shows methodology useful for making a compound of formula Iusing phenyllithium intermediates.

A bromobenzene of formula 49 is reacted with n-butyllithium to make thecorresponding intermediate organolithium reagent which is then reactedwith a benzaldehyde of formula 50 to provide a diphenyl hydroxy compoundof Formula 51. Hydroxy compound 51 is then treated with an oxidizingagent to provide an intermediate benzophenone compound of Formula 46which is reacted with an appropriate phosphorane 47 or phosphonate 48,as depicted in Scheme 1 herein above, in a Wittig reaction to provide acompound of Formula I.

Suitable oxidizing agents useful in the conversion of a compound offormula 51 to a compound of formula 46 include, but are not limited topyridinium chlorochromate (PCC), pyridinium dichromate (PDC), JonesReagent, Dess-Martin periodinane, MnO₂ and tetra-n-propylperruthenate(TPAP).

In a preferred embodiment the oxidizing agent is PCC.

It will be obvious to one of ordinary skill in the art of organicchemistry how to prepare the scope of the compounds of the inventionusing the methodology depicted in Schemes 1-4 and by simple chemicaltransformations upon the products obtained using the methodology ofSchemes 1-4.

Compounds of the invention can also be prepared using the procedures setforth in PCT International Publication No. WO 98/06692, published Feb.19, 1998 (see, e.g., page 10, line 25 to page 11, line 3 and Examples1-30) and U.S. Pat. No. 5,929,117, issued Jul. 22, 1999 (see, e.g.,column 7, line 57 to column 8, line 14 and Examples 1-34), each of whichis incorporated by reference herein in its entirety.

Once synthesized, a compound of the invention can be isolated fromchemical precursors or other chemicals using standard purificationtechniques such as, for example, chromatography (e.g., flash columnchromatography and HPLC), asymmetric methods of synthesis,recrystallization and differential solubility.

4.2 Agents Useful In Combination With Compounds of the Invention

The present invention provides methods for preventing, managing,treating, or ameliorating disorders (e.g., proliferative disorders,disorders associated with or characterized by aberrant angiogenesis,disorders prevented, managed or treated by inhibiting or reducing PDE4expression and/or activity or inhibiting or reducing tubulinpolymerization and/or stability, or inflammatory disorders) comprisingadministering to a subject in need thereof or one or more compounds ofthe invention and one or more therapies (e.g., one or more prophylacticor therapeutic agents) other than compounds of the invention.

The present invention also provides compositions comprising one or morecompounds of the invention and one or more prophylactic or therapeuticagents other than compounds of the invention and methods of preventing,managing, treating, or ameliorating a proliferative disorder or aninflammatory disorder utilizing said compositions. Therapeutic orprophylactic agents include, but are not limited to, small molecules,synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g.,DNA and RNA nucleotides including, but not limited to, antisensenucleotide sequences, RNAi, triple helices and nucleotide sequencesencoding biologically active proteins, polypeptides or peptides),antibodies, synthetic or natural inorganic molecules, mimetic agents,and synthetic or natural organic molecules.

Any agent which is known to be useful, or which has been used or iscurrently being used for the prevention, management, treatment, oramelioration of a disorder (e.g., a proliferative disorder, disorderscharacterized by or associated with aberrant angiogenesis, proliferativedisorders, inflammatory disorders and disorders prevented, managed,treated or ameliorated by inhibiting PDE4, or by reducing or inhibitingtubulin polymerization or stability, or an inflammatory disorder) or oneor more symptoms thereof can be used in combination with a compound ofthe invention in accordance with the invention described herein. See,e.g., Gilman et al., Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, Tenth Ed., McGraw-Hill, New York, 2001; The Merck Manualof Diagnosis and Therapy, Berkow, M. D. et al. (eds.), 17th Ed., MerckSharp & Dohme Research Laboratories, Rahway, N.J., 1999; Cecil Textbookof Medicine, 20th Ed., Bennett and Plum (eds.), W. B. Saunders,Philadelphia, 1996 for information regarding prophylactic or therapeuticagents which have been or are currently being used for preventing,treating, managing, or ameliorating proliferative disorders orinflammatory disorders or one or more symptoms thereof. Examples of suchagents include, but are not limited to, anti-inflammatory agents (e.g.,corticosteroids (e.g., prednisone and hydrocortisone), glucocorticoids,steroids, non-steriodal anti-inflammatory drugs (e.g., aspirin,ibuprofen, diclofenac, and COX-2 inhibitors), beta-agonists,anticholinergic agents and methyl xanthines), immunomodulatory agents,gold injections, sulphasalazine, penicillamine, anti-angiogenic agents(e.g., angiostatin, TNF-α antagonists (e.g., anti-TNFα antibodies), andendostatin), anti-fibrotics, antiemetic agents (e.g., metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols,thiethylperazine, thioproperazine and tropisetron), opioids (e.g.,morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone,metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine,lopermide, anileridine, ethoheptazine, piminidine, betaprodine,diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil,levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine,methadone, isomethadone and propoxyphene), hematopoietic colonystimulating factors (e.g., filgrastim, pegfilgrastim sargramostim,molgramostim and epoetin alfa), antiemetic agents (e.g., metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols,thiethylperazine, thioproperazine and tropisetron), dapsone, psoralens(e.g., methoxalen and trioxsalen), antihistamines, anti-malarial agents(e.g., hydroxychloroquine), anti-viral agents, antibiotics (e.g.,dactinomycin (formerly actinomycin), bleomycin, erythomycin, penicillin,mithramycin, and anthramycin (AMC)), vascular targeting agents (e.g.,microtubulin destabilizing drugs, combretastatin A-4 disodium phosphate,ZD6126, AVE8062, Oxi 4503, TZT 1027 and DMXAA), IMiDso and SelCIDs&(Celgene Corporation, New Jersey) (e.g., Revimid, Actimid, and thosedisclosed in U.S. Pat. Nos. 6,075,041; 5,877,200; 5,698,579; 5,703,098;6,429,221; 5,736,570; 5,658,940; 5,728,845; 5,728,844; 6,262,101;6,020,358; 5,929,117; 6,326,388; 6,281,230; 5,635,517; 5,798,368;6,395,754; 5,955,476; 6,403,613; 6,380,239; and 6,458,810, each of whichis incorporated herein by reference).

4.2.1 Immunodulatory Agents Any immunomodulatory agent well-known to oneof skill in the art may be used in the methods and compositions of theinvention.

Examples of immunomodulatory agents include, but are not limited to,proteinaceous agents such as cytokines, peptide mimetics, and antibodies(e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs,Fab or F(ab)₂ fragments or epitope binding fragments), nucleic acidmolecules (e.g., antisense nucleic acid molecules, triple helices andnucleic acid molecules encoding immunomodulatory gene products), smallmolecules, organic compounds, and inorganic compounds. In particular,immunomodulatory agents include, but are not limited to, methothrexate,leflunomide, cyclophosphamide, cytoxan, Immuran, cyclosporine A,minocycline, azathioprine, antibiotics (e.g., FK506 (tacrolimus)),methylprednisolone (MP), corticosteroids, steriods, mycophenolatemofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar,malononitriloamindes (e.g., leflunamide), T cell receptor modulators,and cytokine receptor modulators. Examples of cytokine receptormodulators include, but are not limited to, soluble cytokine receptors(e.g., the extracellular domain of a TNF-α receptor or a fragmentthereof, the extracellular domain of an IL-1β receptor or a fragmentthereof, and the extracellular domain of an IL-6 receptor or a fragmentthereof), cytokines or fragments thereof (e.g., interleukin (IL)-2,IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15,IL-23 TNF-α, TNF-0, interferon (IFN)-α, IFN-β, IFN-γ, and GM-CSF),anti-cytokine receptor antibodies (e.g., anti-IFN receptor antibodies,anti-IL-2 receptor antibodies (e.g., Zenapax (Protein Design Labs)),anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies, anti-IL-10receptor antibodies, anti-IL-12 receptor antibodies, anti-IL-15 receptorantibodies and anti-IL-23 receptor antibodies), anti-cytokine antibodies(e.g., anti-IFN α antibodies, anti-IFN-β antibodies, anti-IFN-γantibodies, anti-TNF-α antibodies, anti-IL-1βantibodies, anti-IL-2antibodies, anti-IL-4 antibodies, anti-IL-6 antibodies, anti-IL-8antibodies (e.g., ABX-IL-8 (Abgenix)), anti-IL-9 antibodies, anti-IL-10antibodies, anti-IL-12 antibodies and anti-IL-23 antibodies). In aspecific embodiment, a cytokine receptor modulator is IL-4, IL-10, or afragment thereof. In another embodiment, a cytokine receptor modulatoris an anti-IL-1β antibody, anti-IL-6 antibody, anti-IL-12 receptorantibody, or anti-TNF-α antibody. In another embodiment, a cytokinereceptor modulator is the extracellular domain of a TNF-α receptor or afragment thereof. In certain embodiments, a cytokine receptor modulatoris not a TNF-α antagonist.

4.2.2 Anti-Angiogenic Agents

Any anti-angiogenic agent well-known to one of skill in the art can beused in the compositions and methods of the invention. Non-limitingexamples anti-angiogenic agents include proteins, polypeptides,peptides, fusion proteins, antibodies (e.g., human, humanized, chimeric,monoclonal, polyclonal, Fvs, ScFvs, Fab fragments, F(ab)₂ fragments, andantigen-binding fragments thereof) such as antibodies thatimmunospecifically bind to TNF-U, nucleic acid molecules (e.g.,antisense molecules or triple helices), organic molecules, inorganicmolecules, and small molecules that reduce or inhibit angiogenesis. Inparticular, examples of anti-angiogenic agents, include, but are notlimited to, endostatin, angiostatin, apomigren, anti-angiogenicantithrombin III, the 29 kDa N-terminal and a 40 kDa C-terminalproteolytic fragments of fibronectin, a uPA receptor antagonist, the 16kDa proteolytic fragment of prolactin, the 7.8 kDa proteolytic fragmentof platelet factor-4, the anti-angiogenic 24 amino acid fragment ofplatelet factor-4, the anti-angiogenic factor designated 13.40, theanti-angiogenic 22 amino acid peptide fragment of thrombospondin I, theanti-angiogenic 20 amino acid peptide fragment of SPARC, RGD and NGRcontaining peptides, the small anti-angiogenic peptides of laminin,fibronectin, procollagen and EGF, anti-integrin α_(v)β₃ antibodies, acidfibroblast growth factor (aFGF) antagonists, basic fibroblast growthfactor (bFGF) antagonists, vascular endothelial growth factor (VEGF)antagonists (e.g., anti-VEGF antibodies), and VEGF receptor (VEGFR)antagonists (e.g., anti-VEGFR antibodies).

Examples of integrin α_(V)β₃ antagonists include, but are not limitedto, proteinaceous agents such as non-catalytic metalloproteinasefragments, RGD peptides, peptide mimetics, fusion proteins, disintegrinsor derivatives or analogs thereof, and antibodies thatimmunospecifically bind to integrin α_(V)β₃, nucleic acid molecules,organic molecules, and inorganic molecules. Non-limiting examples ofantibodies that immunospecifically bind to integrin α_(V)β₃ include 11D2(Searle). Non-limiting examples of small molecule peptidometric integrinα_(V)β₃ antagonists include S836 (Searle) and S448 (Searle). Examples ofdisintegrins include, but are not limited to, Accutin. The inventionalso encompasses the use of any of the integrin α_(V)β₃ antagonistsdisclosed in the following U.S. Patents and International publicationsin the compositions and methods of the invention: U.S. Pat. Nos.5,652,109; 5,652,110; 5,578,704; 5,149,780; 5,196,511; 5,204,445;5,262,520; 5,306,620; 5,478,725; 5,498,694; 5,523,209; 5,578,704;5,589,570; 5,652,109; 5,652,110; 5,693,612; 5,705,481; 5,753,230;5,767,071; 5,770,565; 5,780,426; 5,817,457; 5,830,678; 5,849,692;5,955,572; 5,985,278; 6,048,861; 6,090,944; 6,096,707; 6,130,231;6,153,628; 6,160,099; and 6,171,58; and International Publication Nos.WO 95/22543; WO 98/33919; WO 00/78815; WO 00/31248; WO 98/46264; WO98/40488; and WO 02/070007, each of which is incorporated herein byreference in its entirety.

In a specific embodiment of the invention, an anti-angiogenic agent isendostatin. Naturally occurring endostatin consists of the C-terminal˜180 amino acids of collagen XVIII (cDNAs encoding two splice forms ofcollagen XVIII have GenBank Accession Nos. AF18081 and AF18082). Inanother embodiment of the invention, an anti-angiogenic agent is aplasminogen fragment (the coding sequence for plasminogen can be foundin GenBank Accession Nos. NM_(—)000301 and A33096). Angiostatin peptidesnaturally include the four kringle domains of plasminogen, kringle 1through kringle 4. It has been demonstrated that recombinant kringle 1,2 and 3 possess the anti-angiogenic properties of the native peptide,whereas kringle 4 has no such activity (Cao et al., 1996, J. Biol. Chem.271:29461-29467). Accordingly, the angiostatin peptides comprises atleast one and preferably more than one kringle domain selected from thegroup consisting of kringle 1, kringle 2 and kringle 3. In a specificembodiment, the anti-angiogenic peptide is the 40 kDa isoform of thehuman angiostatin molecule, the 42 kDa isoform of the human angiostatinmolecule, the 45 kDa isoform of the human angiostatin molecule, or acombination thereof. In another embodiment, an anti-angiogenic agent isthe kringle 5 domain of plasminogen, which is a more potent inhibitor ofangiogenesis than angiostatin (angiostatin comprises kringle domains1-4). In another embodiment of the invention, an anti-angiogenic agentis antithrombin III. Antithrombin III, which is referred to hereinafteras antithrombin, comprises a heparin binding domain that tethers theprotein to the vasculature walls, and an active site loop whichinteracts with thrombin. When antithrombin is tethered to heparin, theprotein elicits a conformational change that allows the active loop tointeract with thrombin, resulting in the proteolytic cleavage of saidloop by thrombin. The proteolytic cleavage event results in anotherchange of conformation of antithrombin, which (i) alters the interactioninterface between thrombin and antithrombin and (ii) releases thecomplex from heparin (Carrell, 1999, Science 285:1861-1862, andreferences therein). O'Reilly et al. (1999, Science 285:1926-1928) havediscovered that the cleaved antithrombin has potent anti-angiogenicactivity. Accordingly, in one embodiment, an anti-angiogenic agent isthe anti-angiogenic form of antithrombin. In another embodiment of theinvention, an anti-angiogenic agent is the 40 kDa and/or 29 kDaproteolytic fragment of fibronectin.

In another embodiment of the invention, an anti-angiogenic agent is aurokinase plasminogen activator (uPA) receptor antagonist. In one modeof the embodiment, the antagonist is a dominant negative mutant of uPA(see, e.g., Crowley et al., 1993, Proc. Natl. Acad. Sci. USA90:5021-5025). In another mode of the embodiment, the antagonist is apeptide antagonist or a fusion protein thereof (Goodson et al., 1994,Proc. Natl. Acad. Sci. USA 91:7129-7133). In yet another mode of theembodiment, the antagonist is a dominant negative soluble uPA receptor(Min et al., 1996, Cancer Res. 56:2428-2433). In another embodiment ofthe invention, an anti-angiogenic agent is the 16 kDa N-terminalfragment of prolactin, comprising approximately 120 amino acids, or abiologically active fragment thereof (the coding sequence for prolactincan be found in GenBank Accession No. NM_(—)000948). In anotherembodiment of the invention, an anti-angiogenic agent is the 7.8 kDaplatelet factor-4 fragment. In another embodiment of the invention, ananti-angiogenic agent is a small peptide corresponding to theanti-angiogenic 13 amino acid fragment of platelet factor-4, theanti-angiogenic factor designated 13.40, the anti-angiogenic 22 aminoacid peptide fragment of thrombospondin I, the anti-angiogenic 20 aminoacid peptide fragment of SPARC, the small anti-angiogenic peptides oflaminin, fibronectin, procollagen, or EGF, or small peptide antagonistsof integrin α_(b)β₃ or the VEGF receptor. In another embodiment, thesmall peptide comprises an RGD or NGR motif. In certain embodiments, ananti-angiogenic agent is a TNF-α antagonist. In other embodiments, ananti-angiogenic agent is not a TNF-α antagonist.

Nucleic acid molecules encoding proteins, polypeptides, or peptides withanti-angiogenic activity, or proteins, polypeptides or peptides withanti-angiogenic activity can be administered to a subject with adisorder (e.g., a disorder characterized by or associated with aberrantangiogenesis, a proliferative disorder, an inflammatory disorder or adisorder prevented, managed, treated or ameliorated by inhibiting PDE4,or by reducing or inhibiting tubulin polymerization or stability) inaccordance with the methods of the invention. Further, nucleic acidmolecules encoding derivatives, analogs, fragments, or variants ofproteins, polypeptides, or peptides with anti-angiogenic activity, orderivatives, analogs, fragments, or variants of proteins, polypeptides,or peptides with anti-angiogenic activity can be administered to asubject with a disorder (e.g., a disorder characterized by or associatedwith aberrant angiogenesis, a proliferative disorder, an inflammatorydisorder or a disorder prevented, managed, treated or ameliorated byinhibiting PDE4, or by reducing or inhibiting tubulin polymerization orstability) in accordance with the methods of the invention. Preferably,such derivatives, analogs, variants, and fragments retain theanti-angiogenic activity of the full-length, wild-type protein,polypeptide, or peptide.

Proteins, polypeptides, or peptides that can be used as anti-angiogenicagents can be produced by any technique well-known in the art ordescribed herein. Proteins, polypeptides or peptides withanti-angiogenic activity can be engineered so as to increase the in vivohalf-life of such proteins, polypeptides, or peptides utilizingtechniques well-known in the art or described herein. Preferably,anti-angiogenic agents that are commercially available are used in thecompositions and methods of the invention. The anti-angiogenic activityof an agent can be determined in vitro and/or in vivo by any techniquewell-known to one skilled in the art or described herein.

Anti-angiogenic agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.2.3 TNF-α Antagonists

Any TNF-α antagonist well-known to one of skill in the art can be usedin the compositions and methods of the invention. Non-limiting examplesof TNF-α antagonists include proteins, polypeptides, peptides, fusionproteins, antibodies (e.g., human, humanized, chimeric, monoclonal,polyclonal, Fvs, ScFvs, Fab fragments, F(ab)₂ fragments, andantigen-binding fragments thereof) such as antibodies thatimmunospecifically bind to TNF-α, nucleic acid molecules (e.g.,antisense molecules or triple helices), organic molecules, inorganicmolecules, and small molecules that block, reduce, inhibit or neutralizea function, an activity and/or the expression of TNF-α. In variousembodiments, a TNF-α antagonist reduces the function, activity and/orexpression of TNF-α by at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95% or atleast 99% relative to a control such as phosphate buffered saline (PBS).

Examples of antibodies that immunospecifically bind to TNF-α include,but are not limited to, infliximab (REMICADE®; Centacor), D2E7 (AbbottLaboratories/Knoll Pharmaceuticals Co., Mt. Olive, N.J.), CDP571 whichis also known as HUMICADE™ and CDP-870 (both of Celltech/Pharmacia,Slough, U.K.), and TN3-19.12 (Williams et al., 1994, Proc. Natl. Acad.Sci. USA 91: 2762-2766; Thorbecke et al., 1992, Proc. Natl. Acad. Sci.USA 89:7375-7379). The present invention also encompasses the use of theantibodies that immunospecifically bind to TNF-α disclosed in thefollowing U.S. Patents in the compositions and methods of the invention:U.S. Pat. Nos. 5,136,021; 5,147,638; 5,223,395; 5,231,024; 5,334,380;5,360,716; 5,426,181; 5,436,154; 5,610,279; 5,644,034; 5,656,272;5,658,746; 5,698,195; 5,736,138; 5,741,488; 5,808,029; 5,919,452;5,958,412; 5,959,087; 5,968,741; 5,994,510; 6,036,978; 6,114,517; and6,171,787; each of which are herein incorporated by reference in theirentirety. Examples of soluble TNF-α receptors include, but are notlimited to, sTNF-R1 (Amgen), etanercept (ENBREL™; Immunex) and its rathomolog RENBREL™, soluble inhibitors of TNF-α derived from TNFrI, TNFrII(Kohno et al., 1990, Proc. Natl. Acad. Sci. USA 87:8331-8335), and TNF-αInh (Seckinger et al., 1990, Proc. Natl. Acad. Sci. USA 87:5188-5192).

In one embodiment, a TNF-α antagonist used in the compositions andmethods of the invention is a soluble TNF-α receptor. In a specificembodiment, a TNF-α antagonist used in the compositions and methods ofthe invention is etanercept (ENBREL™; Immunex) or a fragment, derivativeor analog thereof. In another embodiment, a TNF-α antagonist used in thecompositions and methods of the invention is an antibody thatimmunospecifically binds to TNF-α. In a specific embodiment, a TNF-αantagonist used in the compositions and methods of the invention isinfliximab (REMICADE®; Centacor) a derivative, analog or antigen-bindingfragment thereof.

Other TNF-α antagonists encompassed by the invention include, but arenot limited to, IL-10, which is known to block TNF-α production viainterferon γ-activated macrophages (Oswald et al. 1992, Proc. Natl.Acad. Sci. USA 89:8676-8680), TNFR-IgG (Ashkenazi et al., 1991, Proc.Natl. Acad. Sci. USA 88:10535-10539), the murine product TBP-1(Serono/Yeda), the vaccine CytoTAb (Protherics), antisensemolecule104838 (ISIS), the peptide RDP-58 (SangStat), thalidomide(Celgene), CDC-801 (Celgene), DPC-333 (Dupont), VX-745 (Vertex),AGIX-4207 (AtheroGenics), ITF-2357 (Italfarmaco), NPI-13021-31 (Nereus),SCIO-469 (Scios), TACE targeter (Immunix/AHP), CLX-120500 (Calyx),Thiazolopyrim (Dynavax), auranofin (Ridaura) (SmithKline BeechamPharmaceuticals), quinacrine (mepacrine dichlorohydrate), tenidap(Enablex), Melanin (Large Scale Biological), and anti-p38 MAPK agents byUriach.

TNF-α antagonists and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.2.4 Anti-Inflammatory Agents

Anti-inflammatory agents have exhibited success in treatment ofproliferative disorders or inflammatory disorders and are now a commonand a standard treatment for such disorders as well as others. Anyanti-inflammatory therapy (e.g., an anti-inflammatory agent) well-knownto one of skill in the art can be used in the compositions and methodsof the invention. Non-limiting examples of anti-inflammatory agentsinclude non-steroidal anti-inflammatory drugs (NSAIDs), steroidalanti-inflammatory drugs, beta-agonists, anticholingeric agents,antihistamines (e.g., ethanolamines, ethylenediamines, piperazines, andphenothiazine), and methyl xanthines. Examples of NSAIDs include, butare not limited to, aspirin, ibuprofen, salicylates, acetominophen,celecoxib (CELEBREX™), diclofenac (VOLTAREN™), etodolac (LODINE™),fenoprofen (NALFON™), indomethacin (INDOCIN™), ketoralac (TORADOL™),oxaprozin (DAYPRO™), nabumentone (RELAFEN™), sulindac (CLINORIL™),tolmentin (TOLECTIN™), rofecoxib (VIOXX™), naproxen (ALEVE™, NAPROSYN™),ketoprofen (ACTRON™) and nabumetone (RELAFEN™). Such NSAIDs function byinhibiting a cyclooxygenase enzyme (e.g., COX-1 and/or COX-2). Examplesof steroidal anti-inflammatory drugs include, but are not limited to,glucocorticoids, dexamethasone (DECADRON™), cortisone, hydrocortisone,prednisone (DELTASONE™), prednisolone, triamcinolone, azulfidine, andeicosanoids such as prostaglandins, thromboxanes, and leukotrienes.

Anti-inflammatory agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.2.5 Anti-Cancer Agents

Any therapy (e.g., any prophylactic or therapeutic agent) which is knownto be useful, has been used, or is currently being used for theprevention, treatment, management, or amelioration of one or moresymptoms associated with a proliferative disorder, such as cancer can beused in compositions and method of the invention. Therapeutic orprophylactic agents include, but are not limited to, peptides,polypeptides, fusion proteins, nucleic acid molecules, small molecules,mimetic agents, synthetic drugs, inorganic molecules, and organicmolecules. Non-limiting examples of cancer therapies includechemotherapies, radiation therapies, hormonal therapies, and/orbiological therapies/immunotherapies.

In certain embodiments, the anti-cancer agent is an immunomodulatoryagent such as a chemotherapeutic agent. In other embodiments, theanti-cancer agent is not an immunomodulatory agent. In specificembodiments, the anti-cancer agent is an anti-angiogenic agent. In otherembodiments, the anti-cancer agent is not an anti-angiogenic agent.

Examples of anti-cancer agents include, but are not limited to:acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bisphosphonates (e.g., pamidronate (Aredria), sodium clondronate(Bonefos), zoledronic acid (Zometa), alendronate (Fosamax), etidronate,ibandomate, cimadronate, risedromate, and tiludromate); bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin-2 (includingrecombinant interleukin 2, or rIL2), interferon alpha-2a; interferonalpha-2b; interferon alpha-nl; interferon alpha-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; anti-CD2 antibodies;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; and zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-i; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflomithine; elemene; emitefur; epirubicin; epothilone A; epothilone B;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; HMG CoAreductase inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin,lescol, lupitor, lovastatin, rosuvastatin, and simvastatin); hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; LFA-3TIP(Biogen, Cambridge, Mass.; U.S. Pat. No. 6,162,432); liarozole; linearpolyamine analogue; lipophilic disaccharide peptide; lipophilic platinumcompounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol;lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;5-fluorouracil; leucovorin; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide;tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietinmimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;titanocene bichloride; topsentin; toremifene; totipotent stem cellfactor; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; vector system, erythrocyte genetherapy; thalidomide; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vorozole; zanoterone; zeniplatin; zilascorb;and zinostatin stimalamer.

In more particular embodiments, the present invention also comprises theadministration of a compound of the invention in combination with theadministration of one or more therapies such as, but not limited toanti-cancer agents such as those disclosed in Table 2, preferably forthe treatment of breast, ovary, melanoma, prostate, colon and lungcancers. TABLE 2 Therapeutic Agent Dose/Administration/FormulationDoxorubicin Intravenous 60-75 mg/m² on Day 1 21 day intervalshydrochloride (Adriamycin RDF ® and Adriamycin PFS ®) EpirubicinIntravenous 100-120 mg/m² on Day 1 of each 3-4 week cycles hydrochloridecycle or (Ellence ™) divided equally and given on Days 1-8 of the cycleFluorouracil Intravenous How supplied: 5 mL and 10 mL vials (containing250 and 500 mg fluorouracil respectively) Docetaxel Intravenous 60-100mg/m² over 1 hour Once every 3 weeks (Taxotere ®) Paclitaxel Intravenous175 mg/m² over 3 hours Every 3 weeks for (Taxol ®) 4 courses(administered sequentially to doxorubicin- containing combinationchemotherapy) tamoxifen citrate Oral 20-40 mg Daily (Nolvadex ®)(tablet) Dosages greater than 20 mg should be given in divided doses(morning and evening) leucovorin calcium Intravenous or How supplied:Dosage is unclear from text. for injection intramuscular 350 mg vial PDR3610 injection luprolide acetate Single 1 mg (0.2 mL or 20 unit mark)Once a day (Lupron ®) subcutaneous injection Flutamide Oral (capsule)250 mg 3 times a day at 8 hour intervals (Eulexin ®) (capsules contain125 mg (total daily dosage 750 mg) flutamide each) Nilutamide Oral 300mg or 150 mg 300 mg once a day for 30 days (Nilandron ®) (tablet)(tablets contain 50 or 150 mg followed by 150 mg once a day nilutamideeach) Bicalutamide Oral 50 mg Once a day (Casodex ®) (tablet) (tabletscontain 50 mg bicalutamide each) Progesterone Injection USP in sesameoil 50 mg/mL Ketoconazole Cream 2% cream applied once or twice(Nizoral ®) daily depending on symptoms prednisone Oral Initial dosagemay vary from 5 mg (tablet) to 60 mg per day depending on the specificdisease entity being treated. Estramustine Oral 14 mg/kg of body weight(i.e. one Daily given in 3 or 4 divided phosphate sodium (capsule) 140mg capsule for each 10 kg or doses (Emcyt ®) 22 lb of body weight)etoposide or Intravenous 5 mL of 20 mg/mL solution (100 mg) VP-16Dacarbazine Intravenous 2-4.5 mg/kg Once a day for 10 days.(DTIC-Dome ®) May be repeated at 4 week intervals Polifeprosan 20 withwafer placed in 8 wafers, each containing 7.7 mg carmustine implantresection of carmustine, for a total of 61.6 mg, (BCNU) cavity if sizeand shape of resection (nitrosourea) cavity allows (Gliadel ®) CisplatinInjection [n/a in PDR 861] How supplied: solution of 1 mg/mL inmulti-dose vials of 50 mL and 100 mL Mitomycin Injection supplied in 5mg and 20 mg vials (containing 5 mg and 20 mg mitomycin) gemcitabine HClIntravenous For NSCLC-2 schedules have 4 week schedule- (Gemzar ®) beeninvestigated and the optimum Days 1, 8 and 15 of each 28-day schedulehas not been determined cycle. Cisplatin intravenously 4 week schedule-at 100 mg/m² on day 1 after the administration intravenously at infusionof Gemzar. 1000 mg/m² over 30 minutes on 3 3 week schedule- weekschedule- Days 1 and 8 of each 21 day Gemzar administered cycle.Cisplatin at dosage of intravenously at 1250 mg/m² over 100 mg/m²administered 30 minutes intravenously after administration of Gemzar onday 1. Carboplatin Intravenous Single agent therapy: Every 4 weeks(Paraplatin ®) 360 mg/m² I.V. on day 1 (infusion lasting 15 minutes orlonger) Other dosage calculations: Combination therapy withcyclophosphamide, Dose adjustment recommendations, Formula dosing, etc.Ifosamide Intravenous 1.2 g/m² daily 5 consecutive days (Ifex ®) Repeatevery 3 weeks or after recovery from hematologic toxicity TopotecanIntravenous 1.5 mg/m² by intravenous infusion 5 consecutive days,starting on hydrochloride over 30 minutes daily day 1 of 21 day course(Hycamtin ®)

In specific embodiments, radiation therapy comprising the use of x-rays,gamma rays and other sources of radiation to destroy the cancer cells isused in combination with the antibodies of the invention. In preferredembodiments, the radiation treatment is administered as external beamradiation or teletherapy, wherein the radiation is directed from aremote source. In other preferred embodiments, the radiation treatmentis administered as internal therapy or brachytherapy wherein aradioactive source is placed inside the body close to cancer cells or atumor mass.

Cancer therapies and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.2.6 Antibiotics

Antibiotics well known to one of skill in the art can be used in thecompositions and methods of the invention. Non-limiting examples ofantibiotics include penicillin, cephalosporin, imipenem, axtreonam,vancomycin, cycloserine, bacitracin, chloramphenicol, erythromycin,clindamycin, tetracycline, streptomycin, tobramycin, gentamicin,amikacin, kanamycin, neomycin, spectinomycin, trimethoprim, norfloxacin,rifampin, polymyxin, amphotericin B, nystatin, ketocanazole, isoniazid,metronidazole, and pentamidine.

Antibiotics and their dosages, routes of administration and recommendedusage are known in the art and have been described in such literature asthe Physician 's Desk Reference (57th ed., 2003).

4.2.7 Antiviral Agents

Any anti-viral agent well-known to one of skill in the art can be usedin the compositions and the methods of the invention. Non-limitingexamples of anti-viral agents include proteins, polypeptides, peptides,fusion protein antibodies, nucleic acid molecules, organic molecules,inorganic molecules, and small molecules that inhibit or reduce theattachment of a virus to its receptor, the internalization of a virusinto a cell, the replication of a virus, or release of virus from acell. In particular, anti-viral agents include, but are not limited to,nucleoside analogs (e.g., zidovudine, acyclovir, gangcyclovir,vidarabine, idoxuridine, trifluridine, and ribavirin), foscarnet,amantadine, rimantadine, saquinavir, indinavir, ritonavir,alpha-interferons and other interferons, and AZT.

Antiviral agents and their dosages, routes of administration andrecommended usage are known in the art and have been described in suchliterature as the Physician 's Desk Reference (56^(th) ed., 2002).

4.2.8 Vascular Targeting Agents

Any vascular targeting agent well-known to one of skill in the art canbe used in the compositions and methods of the invention (see, e.g.,Thorpe, P. E., Clin. Can. Res. 10:415-427 (2004), incorporated herein byreference in its entirety).

Non-limiting examples of vascular targeting agents include smallmolecule vascular targeting agents (e.g., microtubulin destabilizingdrugs, combretastatin A-4 disodium phosphate, ZD6126, AVE8062, Oxi 4503,TZT 1027 and DMXAA) and ligand-based vascular targeting agentsincluding, but not limited to, fusion proteins (e.g., vascularendothelial growth factor linked to the plant toxin gelonin),immunotoxins (e.g., monoclonal antibodies to endoglin conjugated toricin A), antibodies linked to cytokines and liposomally encapsulateddrugs.

In one embodiment, a ligand-based vascular targeting agent is comprisedof any ligand that binds selectively to a component of a tumor bloodvessel, which is linked (e.g., by a chemical cross-linker or peptidebond) to an agent capable of occluding a tumor blood vessel. Examples ofligands that bind selectively to a component of a tumor blood vesselinclude, but are not limited to, an antibody or peptide directed againsta marker that is selectively up-regulated on tumor tissue endothelialcells compared to normal tissue endothelial cells. Example of markersthat are selectively up-regulated on tumor tissue endothelial cellscompared to normal tissue endothelial cells include, but are not limitedto, cell adhesion molecules induced by inflammatory mediators (e.g.,interleukin (IL)-1) and molecules associated with prothrombotic changesthat occur on tumor vascular endothelium. Examples of agents capable ofoccluding a tumor blood vessel include, but are not limited to,coagulation-inducing proteins (e.g., tissue factor), toxins (e.g.,diphtheria toxin, ricin, gelonin), cytotoxic agents (e.g., doxorubicin,neocarzinostatin), cytokines (e.g., interleukin-2, interleukin-12, tumornecrosis factor-α), apoptosis-induction agents (e.g., RAF-1 gene,mitochondrial-membrane disrupting peptide), radioisotopes (e.g.,iodine-131, actinium-225, bismuth-213) and liposomally encapsulatedeffectors (e.g., arabinofuranosylcytosine derivatives).

Vascular targeting agents and their dosages, routes of administrationand recommended usage are known in the art and have been described insuch literature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.3 Uses of Compounds of the Invention

The present invention is directed to therapies which involveadministering one of more compounds of the invention, or compositionscomprising said compounds to a subject, preferably a human subject, forpreventing, treating, managing, or ameliorating disease or disorder orone or more symptoms thereof. In one embodiment, the invention providesa method of preventing, treating, managing, or ameliorating a disease ordisorder or one or more symptoms thereof, said method comprisingadministering to a subject in need thereof a dose of a prophylacticallyor therapeutically effective amount of one or more compounds of theinvention.

The invention also provides methods of preventing, treating, managing,or ameliorating a disease or disorder or one or more symptoms thereof,said methods comprising administering to a subject in need thereof oneor more of compounds of the invention and one or more therapies (e.g.,one or more prophylactic or therapeutic agents) that are currently beingused, have been used, or are known to be useful in the prevention,treatment or amelioration of one or more symptoms associated with saiddisease or disorder. The prophylactic or therapeutic agents of thecombination therapies of the invention can be administered sequentiallyor concurrently. In a specific embodiment, the combination therapies ofthe invention comprise one or more compounds and at least one othertherapy (e.g., another prophylactic or therapeutic agent) which has thesame mechanism of action as said compounds. In another specificembodiment, the combination therapies of the invention comprise one ormore compounds of the invention and at least one other therapy (e.g.,another prophylactic or therapeutic agent) which has a differentmechanism of action than said compounds. In certain embodiments, thecombination therapies of the present invention improve the prophylacticor therapeutic effect of one or more compounds of the invention byfunctioning together with compounds to have an additive or synergisticeffect. In certain embodiments, the combination therapies of the presentinvention reduce the side effects associated with therapies (e.g.,prophylactic or therapeutic agents).

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject, preferably a human subject, in the samepharmaceutical composition. In alternative embodiments, the prophylacticor therapeutic agents of the combination therapies can be administeredconcurrently to a subject in separate pharmaceutical compositions. Theprophylactic or therapeutic agents may be administered to a subject bythe same or different routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to prevent, treat, manage, or ameliorate one or more symptomsassociated with a disease or disorder. In accordance with the invention,pharmaceutical compositions of the invention may also comprise one ormore prophylactic or therapeutic agents which are currently being used,have been used, or are known to be useful in the prevention, treatmentor amelioration of one or more symptoms associated with a disease ordisorder.

Diseases and disorders which can be prevented, treated, managed, orameliorated by administering an effective amount of one or morecompounds of the invention include, but are not limited to, disorderscharacterized by or associated with aberrant angiogenesis, centralnervous system disorders, proliferative disorders, inflammatorydisorders, autoimmune disorders, disorders prevented, managed, treatedor ameliorated by vascular inhibition (e.g., blocking angiogenesisthrough vascular inhibition) and disorders prevented, managed, treatedor ameliorated by inhibiting and/or reducing the expression and/oractivity of PDE4, or by inhibiting or reducing tubulin polymerization orstability. Examples of disorders characterized or associated withangiogenesis include, but are not limited to, proliferative disorders,such as cancer. Examples of disorders prevented, managed, treated orameliorated by the inhibition or reduction in the expression and/oractivity of PDE4 include, but are not limited to, inflammatory disorderssuch as asthma, inflammation, chronic or acute obstructive pulmonarydisease, chronic or acute pulmonary inflammatory disease, inflammatorybowel disease, Crohn's Disease, Bechet's Disease, HSP, colitis, andinflammation due to reperfusion. Examples of disorders prevented,managed, treated or ameliorated by the inhibition or reduction oftubulin polymerization or stability include, but are not limited to,proliferative disorders such as cancer and noncancerous disorders suchas psoriasis and fibrosis.

In a specific embodiment, the invention provides methods for preventing,managing, treating or ameliorating disorders prevented, managed, treatedor ameliorated by vascular inhibition (e.g., blocking angiogenesisthrough vascular inhibition), disorders prevented, managed, treated orameliorated by inhibiting and/or reducing the expression and/or activityof PDE4, or by inhibiting or reducing tubulin polymerization orstability, cancers refractory to current therapy or cancers which are orhave become multi-drug resistant, comprising administering to a patientin need thereof an effective amount of one of more compounds of formulaI or formula X, or pharmaceutically acceptable salts, solvates orhydrates thereof.

In one embodiment, the cancer is refractory to treatment withcolchicine, a taxane or a vinca alkaloid.

In another specific embodiment, the invention provides methods forpreventing, managing, treating or ameliorating disorders prevented,managed, treated or ameliorated by vascular inhibition (e.g., blockingangiogenesis through vascular inhibition), disorders prevented, managed,treated or ameliorated by inhibiting and/or reducing the expressionand/or activity of PDE4, or by inhibiting or reducing tubulinpolymerization or stability, cancers refractory to current therapy orcancers which are or have become multi-drug resistant, comprisingadministering to a patient in need thereof an effective amount of one ofmore of the following compounds:3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)acrylonitrile, methyl3,3-bis-(3-ethoxy-4-methoxyphenyl)-propenoate, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-propoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3,3-bis-(3-cyclopentoxy-4-methoxyphenyl)-acrylonitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropenoate,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylacrylonitrile,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropene,1-(3-cyclopentoxy-4-methoxyphenyl)-1-phenylpropane,3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-phenylpropanoate,3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanenitrile, methyl3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropanoate,3,3-bis-(3,4-dimethoxyphenyl)-propanenitrile,3,3-bis-(3-ethoxy-4-methoxyphenyl)propanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylacrylonitrile,3-(3-ethoxy-4-methoxyphenyl)-3-naphthylpropanenitrile,3-(3,4-dimethoxyphenyl)-3-phenylpropanenitrile;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile,4,4-bis-(3,4-dimethoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-phenylbut-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-cyclopentoxy-4-methoxyphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(3-indan2-yloxy-4-methoxyphenyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-ethoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)but-3-en-2-one;4-(3-cyclopentoxy-4-methoxyphenyl)-4-(4-pyridyl)butan-2-one; methyl3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enoate; methyl3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanoate;4-(3-ethoxy-4-methoxyphenyl)-4-(2-furyl)but-3-en-2-one;3-(3-ethoxy-4-methoxyphenyl)-3-(2-furyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-ethoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)prop-2-enenitrile;3-(3-cyclopentoxy-4-methoxyphenyl)-3-(4-pyridyl)propanenitrile;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)but-3-en-2-one;4,4-bis-(3,4-dimethoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)butan-2-one;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-prop-1-enylphenyl)butan-2-one;4,4-bis-(3-ethoxy-4-methoxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-prop-2-enenitrile;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pentan-3-one;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)pent-1-en-3-one;1,1-bis-(3,4-dimethoxyphenyl)pentan-3-one;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)-3-phenyl-propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanenitrile;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3-(cyclopentylidenemethyl)-4-methoxyphenyl-3-phenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)propanamide;3,3-bis-(3-(cyclopentylidenemethyl)-4-methoxyphenyl)prop-2-enamide;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)prop-2-enamide;3,3-bis-(3,4-dimethoxyphenyl)prop-2-enamide;3,3-bis-(3-ethoxy-4-methoxyphenyl)propanamide;3,3-bis-(3,4-dimethoxyphenyl)propanamide;4-(3,4-dimethoxyphenyl)-4-(4-methoxy-3-exo-norbornyloxyphenyl)but-3-en-2-one;3-(3,4-dimethoxyphenyl)-3-(4-methoxy-3-exo-norbornyloxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile;3-(4-aminophenyl)-3-(3-ethoxy-4-dimethoxyphenyl)prop-2-enenitrile;3-(3,4-dimethoxyphenyl)-3-(3-ethoxy-4-methoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-phenylacetate;3-phenyl-3-(3′-ethoxy-4-methoxyphenyl)acrylamide;1-(3,4-dimethoxyphenyl)-1-phenylprop-1-ene;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene;1-(3,4-dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)but-1-ene;3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile;3-(3-ethoxy-4-methoxyphenyl)-3-phenylpropionitirle;3-(3,4-dimethxyphenyl)-3-(3′,5′-dimethoxyphenyl)-acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile;3-(3′-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3,4-dimethoxy-3′-aminobenzophenone;3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile;3-(4-aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3,4-dimethoxy-4′aminobenzophenone;3-(3,4-dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile;3-(4-biphenylyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-naphth-2-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-pyridine-4-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-pyridin-2-ylacrylonitrile;3-(3,4-dimethoxyphenyl)-3-(2-furyl)acrylonitrile;3-(3,4-diethylphenyl)-3-phenylacrylonitrile;3-(3,4-diethylphenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile;4-(3-ethoxy-4-methoxyphenyl)-4-phenyl-3-butan-2-one;3-(3,4-dimethoxyphenyl)-3-(naphth-1-yl)acrylonitrile;3-(3,4-dimethoxyphenyl)-3-(2,5-dichlorophenyl)acrylonitrile;2′,6′,3,4-tetramethoxybenzophenone; or a pharmaceutically acceptablesalt, solvate and hydrate thereof.

In one embodiment, 3,4-disubstituted compounds of the invention arepreferred inhibitors of PDE4. In another embodiment, 3,4-dialkoxysubstituted compounds of the invention are preferred inhibitors of PDE4.In another embodiment, 3,4-dimethoxy substituted compounds of theinvention are preferred inhibitors of PDE4.

4.3.1 Proliferative Disorders

Compounds of the invention and compositions comprising said compoundscan be used to prevent, treat, manage, or ameliorate a proliferativedisorder (e.g., cancer) or one or more symptoms thereof. Without beingbound by theory, in one embodiment, a compound of the invention binds toan α- or β-tubulin subunit in a cancer or tumor cell and inhibitstubulin polymerization or stability, thereby disrupting the cancer ortumor cell's ability to replicate. In an alternative embodiment, acompound of the invention binds to an α- or β-tubulin subunit inendothelial cells of a vascularized tumor and causes a change in theshape of these cells. The change in shape of these endothelial cellsresults in constriction of blood vessels that supply a tumor with bloodand oxygen, thereby cause the tumor to shrink or die.

In one embodiment, a compound of the invention binds to an α- orβ-tubulin subunit in a tumor cell tumor cell or cancer cell. In anotherembodiment, a compound of the invention binds to an α- or β-tubulinsubunit in a endothelial cell in a vascularized tumor. In a specificembodiment, a compound of the invention is useful for preventing,managing, treating or ameliorating cancers that are sensitive totubulin-binding agents. In another embodiment, a compound of theinvention is useful for preventing, managing, treating or amelioratingcancers that are resistant to tubulin-binding agents.

In another embodiment, the present invention provides methods forinhibiting proliferation of a cancer cell or tumor cell comprisingcontacting the cancer cell or tumor cell with an effective amount of acompound of the invention. In one embodiment, the cancer cell or tumorcell is resistant to traditional cancer therapy. In another embodiment,the cancer cell or tumor cell is a multi-drug resistant cancer cell ortumor cell.

The present invention provides methods for preventing, treating,managing, or ameliorating one or more symptoms of a non-cancerousdisorder associated with cellular hyperproliferation, particularly ofepithelial cells (e.g., as in asthma, COPD, pulmonary fibrosis,bronchial hyperresponsiveness, psoriasis, lymphoproliferative disorder,and seborrheic dermatitis), and endothelial cells (e.g., as inrestenosis, hyperproliferative vascular disease, Behcet's Syndrome,atherosclerosis, and macular degeneration), said methods comprisingadministering to a subject in need thereof one or more compounds of theinvention. The present invention also provides methods for preventing,managing, treating, or ameliorating a non-cancerous disorder associatedwith cellular hyperproliferation, said methods comprising ofadministering to a subject in need thereof one or more compounds of theinvention and one or more other therapies (e.g., one or more otherprophylactic or therapeutic agents) useful for the prevention,treatment, management, or amelioration of said disorder.

In a specific embodiment, the invention provides methods for preventing,managing, treating, or ameliorating a non-cancerous disorder associatedwith cellular hyperproliferation (e.g., Behcet's Syndrome, sarcoidosis,keloids, pulmonary fibrosis, macular degeneration and renal fibrosis) orone or more symptoms thereof, said methods comprising of administeringto a subject in need thereof a prophylactically or therapeuticallyeffective amount of one or more compounds of the invention. In anotherembodiment, the invention provides methods for preventing, managing,treating, or ameliorating a non-cancerous disorder associated withcellular hyperproliferation (e.g., Behcet's Syndrome, sarcoidosis,keloids, pulmonary fibrosis, renal and fibrosis) or one or more symptomsthereof, said methods comprising of administering to a subject in needthereof a prophylactically or therapeutically effective amount of one ormore compounds of the invention and a prophylactically ortherapeutically effective amount of one or more other therapies (e.g.,one or more prophylactic or therapeutic agents).

The invention encompasses methods for preventing, treating, managing, orameliorating one or more symptoms of a disorder associated with cellularhyperproliferation in a subject refractory to conventional therapies forsuch disorder, said methods comprising administering to subject a doseof a prophylactically or therapeutically effective amount of one or morecompounds of the invention. The present invention also provides methodsfor preventing, managing, treating, or ameliorating a non-cancerousdisorder associated with cellular hyperproliferation in a subjectrefractory to conventional therapies for such disorder, said methodscomprising of administering to a subject in need thereof one or morecompounds of the invention and one or more other therapies (e.g., one ormore other prophylactic or therapeutic agents) useful for theprevention, treatment, management, or amelioration of said disorder.

The present invention provides methods for preventing, treating,managing, or ameliorating cancer or one or more symptoms thereof, saidmethods comprising administering one or more compounds of the inventionto a subject in need thereof. The invention also provides methods forpreventing, treating, managing, or ameliorating cancer in which one ormore compounds of the invention are administered in combination with oneor more other therapies (e.g., prophylactic or therapeutic agents)useful for the prevention, treatment, management, or amelioration ofcancer or a secondary condition.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating cancer or one or more symptomsthereof, said method comprising administering to a subject in needthereof a dose of a prophylactically or therapeutically effective amountof one or more compounds of the invention. In another embodiment, theinvention provides a method of preventing, treating, managing, orameliorating cancer or one or more symptoms thereof, said methodcomprising administering to a subject in need thereof a dose of aprophylactically or therapeutically effective amount of one or morecompounds of the invention and a dose of a prophylactically ortherapeutically effective amount of one or more therapies (e.g., one ormore prophylactic or therapeutic agents) useful for the prevention,treatment, management, or amelioration of cancer, or a secondarycondition (e.g., a viral, bacterial, or fungal infection).

The compounds of the invention are particularly useful as vasculartargeting agents. Without being bound by theory, it is thought that thecompounds of the invention are effective anti-tumor agents due to theirability to occlude blood vessels (e.g., pre-existing blood vessels) oftumors resulting in tumor cell death from ischemia and hemorrhagicnecrosis. Thus, the compounds of the invention are useful for destroyingor disrupting the vascular system of a tumor.

The compounds of the invention are particularly effective as vasculartargeting agents against vessels in the interior of the tumor and,accordingly, are can be synergistically used in combination withanti-tumor agents which are effective against peripheral tumor cells(e.g., anti-angiogenic agents). Also without being limited by theory,due to their ability to target tumor cell vasculature, the compounds ofthe invention are particularly effective against tumor cells inlocations distant from blood vessels where drug penetration is poor.Such tumor cells are more likely to become resistant to radiation anddrug therapy. Thus, the compounds of the invention are particularlyeffective against tumors and tumor cells which are or have becomeresistant to traditional cancer therapies.

In one embodiment, the present invention provides a method fortargeting, blocking or destroying the function of tumor vasculature,said method comprising contacting a tumor with an effective amount of acompound of the invention.

In another embodiment, the present invention provides a method fortargeting, blocking or destroying the endothelium of tumor vessels, saidmethod comprising contacting a tumor with an effective amount of acompound of the invention.

In another embodiment, the present invention provides a method foroccluding pre-existing blood vessels of a tumor, said method comprisingcontacting a tumor with an effective amount of a compound of theinvention.

In another embodiment, the present invention provides a method forkilling a tumor cell, said method comprising contacting a tumor cellwith an effective amount of a compound of the invention.

In another embodiment, the present invention provides a method forcausing acute vascular collapse in a tumor cell, said method comprisingcontacting a tumor cell with an effective amount of a compound of theinvention.

In another embodiment, the present invention provides a method forblocking angiogenesis through vascular inhibition, said methodcomprising contacting a cell with an effective amount of a compound ofthe invention.

In another embodiment, the present invention provides a method ofinhibiting tumor growth through vascular inhibition, said methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

Without being limited by theory, it is thought that because thecompounds of the invention have both vascular targeting activity, whichis particularly effective against central tumor cells, andanti-angioenic activity, which is particuarly effective againstperipheral tumor cells, the compounds of the invention are particularlyuseful in eradicating the majority of a tumor and, in one embodiment,completely eradicating a tumor. Accordingly, the compounds of theinvention are particularly active against tumors due to the synergisticeffect of their dual activity as both vascular targeting agents andanti-angiogenic agents.

The compounds of the invention can be used in an in vitro or ex vivofashion for the management, treatment or amelioration of certaincancers, including, but not limited to leukemias and lymphomas, suchtreatment involving autologous stem cell transplants. This can involve amulti-step process in which the subject's autologous hematopoietic stemcells are harvested and purged of all cancer cells, the patient'sremaining bone-marrow cell population is then eradicated via theadministration of a high dose of a compound of the invention with orwithout accompanying high dose radiation therapy, and the stem cellgraft is infused back into the subject. Supportive care is then providedwhile bone marrow function is restored and the subject recovers.

One or more of the compounds of the invention may be used as a first,second, third, fourth or fifth line of cancer treatment. The inventionprovides methods for preventing, treating, managing, or amelioratingcancer or one or more symptoms thereof in a subject refractory toconventional therapies for such a cancer, said methods comprisingadministering to said subject a dose of a prophylactically ortherapeutically effective amount of one or more compounds of theinvention. A cancer may be determined to be refractory to a therapymeans when at least some significant portion of the cancer cells are notkilled or their cell division arrested in response to the therapy. Sucha determination can be made either in vivo or in vitro by any methodknown in the art for assaying the effectiveness of treatment on cancercells, using the art-accepted meanings of “refractory” in such acontext. In a specific embodiment, a cancer is refractory when thenumber of cancer cells has not been significantly reduced, or hasincreased after treatment.

The invention provides methods for preventing, managing, treating orameliorating cancer or one or more symptoms thereof in a subjectrefractory to existing single agent therapies for such a cancer, saidmethods comprising administering to said subject a dose of aprophylactically or therapeutically effective amount of one or morecompounds of the invention and a dose of a prophylactically ortherapeutically effective amount of one or more therapies (e.g., one ormore prophylactic or therapeutic agents) useful for the prevention,treatment, management, or amelioration of cancer or a secondarycondition. The invention also provides methods for preventing, treating,managing, or ameliorating cancer or a secondary condition byadministering one or more compounds of the invention in combination withany other therapy(ies) (e.g., radiation therapy, chemotherapy orsurgery) to patients who have proven refractory to other treatments butare no longer on this therapy(ies).

In a specific embodiment, the invention provides methods for preventing,managing, treating or ameliorating cancer refractory to colchicine,paclitaxel, docetaxel and/or vinblastine and/or other vinca alkaloids orone or more symptoms thereof, said methods comprising administering to asubject in need thereof a dose of a prophylactically or therapeuticallyeffective amount of one or more compounds of the invention. In anotherembodiment, the invention provides methods for preventing, managing,treating or ameliorating cancer refractory to colchicine, paclitaxel,docetaxel and/or vinblastine or one or more symptoms thereof, saidmethods comprising administering to a subject in need thereof a dose ofa prophylactically or therapeutically effective amount of one or morecompounds of the invention and a dose of a prophylactically ortherapeutically effective amount of one or more other therapies. Inaccordance with this embodiment, the other therapies may be achemotherapeutic agent, an immunomodulatory agent, an anti-angiogenicagent, radiation therapy or surgery.

The invention provides methods for the prevention, treatment,management, or amelioration of a patient having cancer andimmunosuppressed by reason of having previously undergone other cancertherapies. The invention also provides alternative methods for theprevention, treatment, management, or amelioration of cancer wherechemotherapy, radiation therapy, hormonal therapy, and/or biologicaltherapy/immunotherapy has proven or may prove too toxic, i.e., resultsin unacceptable or unbearable side effects, for the subject beingtreated. Further, the invention provides methods for preventing therecurrence of cancer in patients that have been treated and have nodisease activity by administering one or more compounds of theinvention.

Cancers that can be prevented, managed, treated or ameliorated inaccordance with the methods of the invention include, but are notlimited to, neoplasms, tumors (malignant and benign) and metastases, orany disease or disorder characterized by uncontrolled cell growth. Thecancer may be a primary or metastatic cancer. Specific examples ofcancers that can be prevented, managed, treated or ameliorated inaccordance with the methods of the invention include, but are notlimited to, cancer of the head, neck, eye, mouth, throat, esophagus,chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries,kidney, liver, pancreas, and brain. Additional cancers include, but arenot limited to, the following: leukemias such as but not limited to,acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemiassuch as myeloblastic, promyelocytic, myelomonocytic, monocytic,erythroleukemia leukemias and myelodysplastic syndrome, chronicleukemias such as but not limited to, chronic myelocytic (granulocytic)leukemia, chronic lymphocytic leukemia, hairy cell leukemia;polycythemia vera; lymphomas such as but not limited to Hodgkin'sdisease, non-Hodgkin's disease; multiple myelomas such as but notlimited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone and connective tissue sarcomas such as but notlimited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,malignant giant cell tumor, fibrosarcoma of bone, chordoma, periostealsarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma),fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial sarcoma;brain tumors such as but not limited to, glioma, astrocytoma, brain stemglioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, primary brain lymphoma; breast cancer including but notlimited to adenocarcinoma, lobular (small cell) carcinoma, intraductalcarcinoma, medullary breast cancer, mucinous breast cancer, tubularbreast cancer, papillary breast cancer, Paget's disease, andinflammatory breast cancer; adrenal cancer such as but not limited topheochromocytom and adrenocortical carcinoma; thyroid cancer such as butnot limited to papillary or follicular thyroid cancer, medullary thyroidcancer and anaplastic thyroid cancer; pancreatic cancer such as but notlimited to, insulinoma, gastrinoma, glucagonoma, vipoma,somatostatin-secreting tumor, and carcinoid or islet cell tumor;pituitary cancers such as but limited to Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; eyecancers such as but not limited to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; vaginal cancers such as squamous cell carcinoma,adenocarcinoma, and melanoma; vulvar cancer such as squamous cellcarcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, andPaget's disease; cervical cancers such as but not limited to, squamouscell carcinoma, and adenocarcinoma; uterine cancers such as but notlimited to endometrial carcinoma and uterine sarcoma; ovarian cancerssuch as but not limited to, ovarian epithelial carcinoma, borderlinetumor, germ cell tumor, and stromal tumor; esophageal cancers such asbut not limited to, squamous cancer, adenocarcinoma, adenoid cycticcarcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma,melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell)carcinoma; stomach cancers such as but not limited to, adenocarcinoma,fungating (polypoid), ulcerating, superficial spreading, diffuselyspreading, malignant lymphoma, liposarcoma, fibrosarcoma, andcarcinosarcoma; colon cancers; rectal cancers; liver cancers such as butnot limited to hepatocellular carcinoma and hepatoblastoma, gallbladdercancers such as adenocarcinoma; cholangiocarcinomas such as but notlimited to pappillary, nodular, and diffuse; lung cancers such asnon-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; testicular cancers such as but not limited to germinal tumor,seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma,embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sactumor), prostate cancers such as but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers suchas but not limited to squamous cell carcinoma; basal cancers; salivarygland cancers such as but not limited to adenocarcinoma, mucoepidermoidcarcinoma, and adenoidcystic carcinoma; pharynx cancers such as but notlimited to squamous cell cancer, and verrucous; skin cancers such as butnot limited to, basal cell carcinoma, squamous cell carcinoma andmelanoma, superficial spreading melanoma, nodular melanoma, lentigomalignant melanoma, acral lentiginous melanoma; kidney cancers such asbut not limited to renal cell cancer, adenocarcinoma, hypemephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer);Wilms' tumor; bladder cancers such as but not limited to transitionalcell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. Inaddition, cancers include myxosarcoma, osteogenic sarcoma,endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma,hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillarycarcinoma and papillary adenocarcinomas (for a review of such disorders,see Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co.,Philadelphia and Murphy et al., 1997, Informed Decisions: The CompleteBook of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin,Penguin Books U.S.A., Inc., United States of America). It is alsocontemplated that cancers caused by aberrations in apoptosis can also betreated by the methods and compositions of the invention. Such cancersmay include, but not be limited to, follicular lymphomas, carcinomaswith p53 mutations, hormone dependent tumors of the breast, prostate andovary, and precancerous lesions such as familial adenomatous polyposis,and myelodysplastic syndromes.

In a specific embodiment, the cancer that is being prevented, managed,treated or ameliorated in accordance with the method of the invention isprostate cancer, breast cancer, bone cancer, melanoma, lung cancer andovarian cancer. In another embodiment, the cancer that is beingprevented, managed, treated or ameliorated in accordance with themethods of the invention are metastatic tumors including, but notlimited to, tumors that have or may metastasize to the bone(non-limiting examples are prostate, breast and lung cancers that havemetastasized or have the potential to metastasize to the bone), tumorsthat have or may metastasize to the lung, tumors that have or maymetastasize to the brain, and tumors that have or may metastasize toother organs or tissues of a subject. In another embodiment, the cancerthat is being prevented, managed, treated or ameliorated in accordancewith the method of the invention is not associated with TNF-α expressionand/or activity.

4.3.2 Inflammatory Disorders

One or more compounds of the invention and compositions comprising ofsaid compounds can be used to prevent, treat, manage, or ameliorate aninflammatory disorder or one or more symptoms thereof. Compounds of theinvention or compositions comprising said compounds may also beadministered in combination with one or more other therapies (e.g., oneor more other prophylactic or therapeutic agents) useful for theprevention, treatment, management, or amelioration of an inflammatorydisorder or one or more symptoms thereof.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating an inflammatory disorder or one ormore symptoms thereof, said method comprising administering to a subjectin need thereof a dose of a prophylactically or therapeuticallyeffective amount one or more compounds of the invention. In anotherembodiment, the invention provides a method of preventing, treating,managing, or ameliorating an inflammatory disorder or one or moresymptoms thereof, said method comprising administering to a subject inneed thereof a dose of a prophylactically or therapeutically effectiveamount of one or more of compounds of the invention and a dose of aprophylactically or therapeutically effective amount of one or moreother therapies (e.g., one or more other prophylactic or therapeuticagents).

The invention provides methods for preventing, managing, treating orameliorating an inflammatory disorder or one or more symptoms thereof ina subject refractory to conventional therapies (e.g., methotrexate and aTNF-α antagonist (e.g., REMICADE™ or ENBREL™)) for such an inflammatorydisorder, said methods comprising administering to said subject a doseof a prophylactically or therapeutically effective amount of one or morecompounds of the invention. The invention also provides methods forpreventing, treating, managing, or ameliorating an inflammatory disorderor one or more symptoms thereof in a subject refractory to existingsingle agent therapies for such an inflammatory disorder, said methodscomprising administering to said subject a dose of a prophylactically ortherapeutically effective amount of one or more compounds of theinvention and a dose of a prophylactically or therapeutically effectiveamount of one or more other therapies (e.g., one or more otherprophylactic or therapeutic agents). The invention also provides methodsfor preventing, treating, managing, or ameliorating an inflammatorydisorder by administering one or more compounds of the invention incombination with any other therapy(ies) to patients who have provenrefractory to other treatments but are no longer on this therapy(ies).The invention also provides alternative methods for the prevention,treatment, management, or amelioration of an inflammatory disorder whereanother therapy has proven or may prove too toxic, i.e., results inunacceptable or unbearable side effects, for the subject being treated.Further, the invention provides methods for preventing the recurrence ofan inflammatory disorder in patients that have been treated and have nodisease activity by administering one or more compounds of theinvention.

Examples of the inflammatory disorders which can be prevented, managed,treated, or ameliorated in accordance with the methods of the invention,include, but are not limited to, asthma, allergic disorders,inflammatory disorders characterized by type-I mediated inflammation,inflammatory disorders characterized by type-2 mediated inflammation,fibrotic disease (e.g., pulmonary fibrosis), psoraisis, multiplesclerosis, systemic lupus erythrematosis, chronic obstructive pulmonarydisease (COPD), encephilitis, inflammatory bowel disease (e.g., Crohn'sdisease and ulcerative colitis), ischemic reperfusion injury, Gout,Behcet's disease, septic shock, undifferentiated spondyloarthropathy,undifferentiated arthropathy, arthritis, rheumatoid arthritis (uvenileand adult), osteoarthritis, psoriatic arthritis, inflammatoryosteolysis, sepsis, meningitis, and chronic inflammation resulting fromchronic viral or bacteria infections. In a specific embodiment, theinflammatory disorder which is prevented, treated, managed, orameliorated in accordance with the methods of the invention is aninflammatory disorder characterized as a type 2-mediated inflammation.Type 2-mediated inflammation is characterized by eosinophilic andbasophilic tissue infiltration and/or extensive mast cell degranulation,a process dependent on cross-linking of surface-bound IgE. In anotherembodiment, the inflammatory disorder which is prevented, treated,managed, or ameliorated in accordance with the methods of the inventionis asthma, Behcet's disease, arthritis, chronic obstructive pulmonarydisease (COPD), pulmonary fibrosis, renal fibrosis, Gout or allergicdisorders.

In a specific embodiment, an effective amount of one or more compoundsof the invention is administered to a subject in combination with aneffective amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating asthma or one or more symptoms thereof. Non-limitingexamples of such therapies include, but are not limited to, adrenergicstimulants (e.g., catecholamines (e.g., epinephrine, isoproterenol, andisoetharine), resorcinols (e.g., metaproterenol, terbutaline, andfenoterol), saligenins (e.g. salbutamol)), anticholinergics (e.g.,atropine sulfate, atropine methylnitrate, and ipratropium bromide(ATROVEN™)), beta2-agonists (e.g. abuterol (VENTOLINM and PROVENTIL™),bitolterol (TORNALATE™), levalbuterol (XOPONEX™), metaproterenol(ALUPENTrm), pirbuterol (MAXAIR™), terbutlaine (BRETHAIRE™ andBRETHINE™), albuterol (PROVENTIL™, REPETABS™, and VOLMAX™), formoterol(FORADIL AEROLIZER™), and salmeterol (SEREVENTrm and SEREVENT DISKUS™)),corticosteroids (e.g., methlyprednisolone (MEDROL™), prednisone(PREDNISONE™ and DELTASONE™), and prednisolone (PRELONE™, PEDIAPRED™)),glucocorticoids (e.g. oral steroids or other systemic or oral steroids,and inhaled glucocoritcoids), other steroids, immunosuppressant agents(e.g. methotrexate and gold salts), leukotriene modifiers (e.g.,montelukast (SINGULAIR™), zafirlukast (ACCOLATE™), and zileuton(ZYFLO™)), mast cell stabilizers (e.g., cromolyn sodium (INTAL™) andnedocromil sodium (TILADE™)), methylxanthines (e.g., theophylline(UNIPHYL™, THEO-DUR™, SLO-BID™, AND TEHO-42™)), and mucolytic agents(e.g., acetylcysteine)).

In a specific embodiment, an effective amount of one or more compoundsof the invention is administered to a subject in combination with aneffective amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating allergies or one or more symptoms thereof. Non-limitingexamples of therapies include antimediator drugs (e.g., antihistamine,see Table 3), corticosteroids, decongestants, sympathomimetic drugs(e.g., α-adrenergic and β-adrenergic drugs), theophylline and itsderivatives, glucocorticoids, and immunotherapies (e.g., repeatedlong-term injection of allergen, short course desensitization, and venomimmunotherapy). TABLE 3 H₁ Antihistamines Chemical class andrepresentative drugs Usual daily dosage Ethanolamine 25-50 mg every 4-6hours Diphehydramine 0.34-2.68 mg every 12 hours ClemastineEthylenediamine 25-50 mg every 4-6 hours Tripelennamine Alkylamine 4 mgevery 4-6 hours; or 8-12 mg of SR Brompheniramine form every 8-12 hourChlorpheniramine 4 mg every 4-6 hours; or 8-12 mg of SR Triprolidine(1.25 mg/5 ml) form every 8-12 hour 2.5 mg every 4-6 hours Phenothiazine25 mg at bedtime Promethazine Piperazine 25 mg every 6-8 hoursHydroxyzine Piperidines 10 mg/d Astemizole (nonsedating) 1-2 mg every 12hours Azatadine 10 mg/d Cetirzine 4 mg every 6-8 hour Cyproheptadine 60mg every 12 hours Fexofenadine (nonsedating) 10 mg every 24 hoursLoratidine (nonsedating)

In a specific embodiment, an effective amount of one or more compoundsof the invention is administered to a subject in combination with aneffective amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating COPD or one or more symptoms thereof. Non-limiting examplesof such therapies include, but are not limited to, bronchodilators (e.g.short-acting β₂-adrenergic agonist (e.g., albuterol, pirbuterol,terbutaline, and metaproterenol), long-acting β₂-adrenergic agonists(e.g., oral sustained-release albuterol and inhaled salmeterol),anticholinergics (e.g., ipratropium bromide), and theophylline and itsderivatives (therapeutic range for theophylline is preferably 10-20μg/mL)), glucocorticoids, exogenous α₁AT (e.g., α₁AT derived from pooledhuman plasma administered intravenously in a weekly dose of 60 mg/kg),oxygen, lung transplantation, lung volume reduction surgery,endotracheal intubation, ventilation support, yearly influenza vaccineand pneumococcal vaccination with 23-valent polysaccharide, exercise,and smoking cessation.

In a specific embodiment, an effective amount of one or more compoundsof the invention is administered to a subject in combination with aneffect amount of one or more therapies (e.g., prophylactic ortherapeutic agents) useful in preventing, treating, managing, orameliorating pulmonary fibrosis or one or more symptoms thereof.Non-limiting examples of such therapies include, oxygen, corticosteroids(e.g., daily administration of prednisone beginning at 1-1.5 mg/kg/d (upto 100 mg/d) for six weeks and tapering slowly over 3-6 months to aminimum maintenance dose of 0.25 mg/kg/d), cytotoxic drugs (e.g.,cyclophosphamide at 100-120 mg orally once daily and azathioprine at 3mg/kg up to 200 mg orally once daily), bronchodilators (e.g., short- andlong-acting β₂-adrenergic agonists, anticholinergics, and theophyllineand its derivatives), and antihistamines (e.g., diphenhydramine anddoxylamine).

Anti-inflammatory therapies and their dosages, routes of administrationand recommended usage are known in the art and have been described insuch literature as the Physician 's Desk Reference (57^(th) ed., 2003).

4.3.3 Central Nervous System Disorders

One or more compounds of the invention and compositions comprising ofsaid compounds can be used to prevent, treat, manage, or ameliorate acentral nervous system disorder or one or more symptoms thereof.Compounds of the invention or compositions comprising said compounds mayalso be administered in combination with one or more other therapies(e.g., one or more other prophylactic or therapeutic agents) useful forthe prevention, treatment, management, or amelioration of a centralnervous system disorder or one or more symptoms thereof.

Central nervous system disorders include, but are not limited to,Parkinson's disease; bradykinesia; muscle rigidity; parkinsonian tremor;parkinsonian gait; motion freezing; depression; defective long-termmemory, Rubinstein-Taybi syndrome (RTS); dementia; sleep disorders;postural instability; hypokinetic disorders; inflammation; synucleindisorders; multiple system artrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranculear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease; Alzheimer disease with parkinsonism;genetic disorders that can have parkinsonian features; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; Huntingtondisease; prion disease; hyperkinetic disorders; chorea; ballismus;dystonia tremors; Amyotrophic Lateral Sclerosis (ALS); CNS trauma andmyoclonus.

In particular embodiments of the invention, a compound of the inventionis used, administered, or formulated with one or more second activeingredients to treat, prevent or manage central nervous systemdisorders. Examples of the second active ingredients include but are notlimited to dopamine agonists, Levodopa, compounds used to augmentLevodopa therapy such as monoamine oxidase inhibitors (MAO) andcatechol-O-methyltransferase inhibitors (COMT), amantadine,anticholinergics, antiemetics, and other standard therapies for centralnervous system disorders. In another example, the second activeingredients are anti-inflammatory agents, including, but not limited to,nonsteroidal anti-inflammatory drugs (NSAIDs), Methotrexate,Leflunomide, antimalarial drugs and sulfasalazine, gold salts,glucocorticoids, immunosuppresive agents, and other standard therapiesfor central nervous system disorders.

4.4 Compositions and Methods for Administering Therapies

The present invention provides compositions for the treatment,prophylaxis, and amelioration of disorders characterized by orassociated with aberrant angiogenesis, proliferative disorders,inflammatory disorders and disorders prevented, managed, treated orameliorated by the inhibition or reduction in expression and/or activityof PDE4 or the inhibition or reduction in tubulin polymerization orstability. In a specific embodiment, a composition comprises one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof. In another embodiment, a composition of theinvention comprises one or more prophylactic or therapeutic agents otherthan a compound of the invention, or a pharmaceutically acceptable salt,solvate or hydrate thereof, said prophylactic or therapeutic agentsknown to be useful for, or having been or currently being used in theprevention, treatment, management, or amelioration of a disorder (e.g.,a disorder characterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability) or one ormore symptoms thereof. In another embodiment, a composition of theinvention comprises one or more compounds of the invention, or apharmaceutically acceptable salt, solvate, or hydrate thereof, and oneor more prophylactic or therapeutic agents, said prophylactic ortherapeutic agents known to useful, or having been or currently beingused in the prevention, treatment or amelioration of a disorder (e.g., adisorder characterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability) or one ormore symptoms thereof.

In a specific embodiment, a composition comprises one or more compoundsof the invention, or a pharmaceutically acceptable salt, solvate, orhydrate thereof, and one or more immunomodulatory agents. In anotherembodiment, a composition comprises one or more compounds of theinvention, or a pharmaceutically acceptable salt, solvate, or hydratethereof, and one or more anti-angiogenic agents, wherein theanti-angiogenic agents are not a compounds of the invention. In anotherembodiment, a composition comprises one or more compounds of theinvention, or a pharmaceutically acceptable salt, solvate, or hydratethereof, and one or more anti-inflammatory agents, wherein theanti-inflammatory agents are not compounds of the invention. In anotherembodiment, a composition comprises one or more compounds of theinvention, or a pharmaceutically acceptable salt, solvate, or hydratethereof, and one or more anti-cancer agents, wherein the anti-canceragents are not compounds of the invention. In accordance with thisembodiment, the anti-cancer agent may or may not be an immunomodulatoryagent or an anti-angiogenic agent. In another embodiment, a compositioncomprises one or more compounds of the invention, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, and one or more anti-viralagents. In another embodiment, a composition comprising one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, or hydrate thereof, or one or more antibiotics. In yet anotherembodiment, a composition comprises one or more compounds of theinvention, or a pharmaceutically acceptable salt, solvate, or hydratethereof, and any combination of one, two, three, or more of each of thefollowing prophylactic or therapeutic agents: an immunomodulatory agent,an anti-angiogenic agent, an anti-cancer agent other than animmunomodulatory agent or anti-angiogenic agent, an anti-inflammatoryagent, an anti-viral agent, or an anti-bacterial agent (e.g., anantibiotic).

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms of the invention comprise aprophylactically or therapeutically effective amount of one or moreprophylactic or therapeutic agents (e.g., a compound of the invention,or other prophylactic or therapeutic agent), and a typically one or morepharmaceutically acceptable carriers or excipients. In a specificembodiment and in this context, the term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with whichthe therapeutic is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a preferred carrier whenthe pharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Examples of suitable pharmaceutical carriers are described in“Remington's Pharmaceutical Sciences” by E. W. Martin.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patientand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP)SP (XXI)/NF (XVI). In general, lactose-freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, tablets, pills, capsules,powders, sustained-release formulations and the like. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such compositions and dosage forms willcontain a prophylactically or therapeutically effective amount of aprophylactic or therapeutic agent preferably in purified form, togetherwith a suitable amount of carrier so as to provide the form for properadministration to the patient. The formulation should suit the mode ofadministration. In a preferred embodiment, the pharmaceuticalcompositions or single unit dosage forms are sterile and in suitableform for administration to a subject, preferably an animal subject, morepreferably a mammalian subject, and most preferably a human subject.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, intra-tumoral,intra-synovial and rectal administration. In a specific embodiment, thecomposition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, oral, intranasal or topical administration to humanbeings. In a preferred embodiment, a pharmaceutical composition isformulated in accordance with routine procedures for subcutaneousadministration to human beings. Typically, compositions for intravenousadministration are solutions in sterile isotonic aqueous buffer. Wherenecessary, the composition may also include a solubilizing agent and alocal anesthetic such as lignocane to ease pain at the site of theinjection. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to apatient, including suspensions (e.g., aqueous or non-aqueous liquidsuspensions, oil-in-water emulsions, or a water-in-oil liquidemulsions), solutions, and elixirs; liquid dosage forms suitable forparenteral administration to a patient; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disorder may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Also, the therapeutically effective dosage form may vary among differenttypes of cancer. Similarly, a parenteral dosage form may contain smalleramounts of one or more of the active ingredients it comprises than anoral dosage form used to treat the same disease or disorder. These andother ways in which specific dosage forms encompassed by this inventionwill vary from one another will be readily apparent to those skilled inthe art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Generally, the ingredients of compositions of the invention are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the composition is to be administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration. Typical dosage forms of the invention comprise acompound of the invention, or a pharmaceutically acceptable salt,solvate or hydrate thereof lie within the range of from about 1 mg toabout 1000 mg per day, given as a single once-a-day dose in the morningbut preferably as divided doses throughout the day taken with food.

4.4.1 Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington 's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

4.4.2 Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

4.4.4 Transdermal, Topical & Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington 'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington 'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.4.5 Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of adisorder (e.g., a disorder characterized by or associated with aberrantangiogensis, a proliferative disorder, an inflammatory disorder or adisorder prevented, managed, treated or ameliorated by inhibiting orreducing PDE4 or inhibiting or reducing tubulin polymerization orstability, or by reducing or inhibiting tubulin polymerization orstability), or one or more symptoms thereof will vary with the natureand severity of the disease or condition, and the route by which theactive ingredient is administered. The frequency and dosage will alsovary according to factors specific for each patient depending on thespecific therapy (e.g., therapeutic or prophylactic agents)administered, the severity of the disorder, disease, or condition, theroute of administration, as well as age, body, weight, response, and thepast medical history of the patient. Effective doses may be extrapolatedfrom dose-response curves derived from in vitro or animal model testsystems. Suitable regiments can be selected by one skilled in the art byconsidering such factors and by following, for example, dosages reportedin the literature and recommended in the Physician 's Desk Reference(57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compoundsof the invention are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a patient isadministered multiple dosages of a compound of the invention, not all ofthe dosages need be the same. For example, the dosage administered tothe patient may be increased to improve the prophylactic or therapeuticeffect of the compound or it may be decreased to reduce one or more sideeffects that a particular patient is experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a disorder (e.g., a disorder characterized by orassociated with aberrant angiogensis, a proliferative disorder, aninflammatory disorder or a disorder prevented, managed, treated orameliorated by inhibiting PDE4, or by reducing or inhibiting tubulinpolymerization or stability), or one or more symptoms thereof in apatient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg,10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg,or 200 mg/kg or more of a patient's body weight. In another embodiment,the dosage of the composition of the invention or a compound of theinvention administered to prevent, treat, manage, or ameliorate adisorder (e.g., a disorder characterized by or associated with aberrantangiogensis, a proliferative disorder, an inflammatory disorder or adisorder prevented, managed, treated or ameliorated by inhibiting PDE4,or by reducing or inhibiting tubulin polymerization or stability), orone or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg,0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to2.5 mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or ameliorate a disorder (e.g., a disordercharacterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability), or one ormore symptoms thereof can be used in the combination therapies of theinvention. Preferably, dosages lower than those which have been or arecurrently being used to prevent, treat, manage, or ameliorate a disorder(e.g., a disorder characterized by or associated with aberrantangiogensis, a proliferative disorder, an inflammatory disorder or adisorder prevented, managed, treated or ameliorated by inhibiting PDE4,or by reducing or inhibiting tubulin polymerization or stability), orone or more symptoms thereof are used in the combination therapies ofthe invention. The recommended dosages of agents currently used for theprevention, treatment, management, or amelioration of a disorder (e.g.,a disorder characterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability), or one ormore symptoms thereof can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003,Medical Economics Co., Inc., Montvale, N.J., which are incorporatedherein by reference in its entirety.

In various embodiments, the therapies (e.g., prophylactic or therapeuticagents) are administered less than 5 minutes apart, less than 30 minutesapart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 11 hours apart, at about 11 hours to about 12 hours apart, atabout 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hoursto 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hoursapart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hoursto 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hourspart. In preferred embodiments, two or more therapies (e.g.,prophylactic or therapeutic agents) are administered within the samepatent visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a disorder (e.g., a disordercharacterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability), or one ormore symptoms thereof, said methods comprising administering to asubject in need thereof a dose of at least 150 μg/kg, preferably atleast 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg,at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or atleast 200 mg/kg or more of one or more compounds of the invention onceevery 3 days, preferably, once every 4 days, once every 5 days, onceevery 6 days, once every 7 days, once every 8 days, once every 10 days,once every two weeks, once every three weeks, or once a month.

The present invention provides methods of preventing, treating,managing, or preventing a disorder (e.g., a disorder characterized by orassociated with aberrant angiogensis, a proliferative disorder, aninflammatory disorder or a disorder prevented, managed, treated orameliorated by inhibiting PDE4, or by reducing or inhibiting tubulinpolymerization or stability), or one or more symptoms thereof, saidmethod comprising: (a) administering to a subject in need thereof one ormore doses of a prophylactically or therapeutically effective amount ofone or more compounds of the invention; and (b) monitoring the meanabsolute lymphocyte count in said subject after administration of acertain number of doses of the said compounds of the invention.Moreover, preferably, said certain number of doses is 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or 12 of a prophylactically or therapeutically effectiveamount of the one or more compounds of the invention.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a disorder (e.g., a disordercharacterized by or associated with aberrant angiogensis, aproliferative disorder, an inflammatory disorder or a disorderprevented, managed, treated or ameliorated by inhibiting PDE4, or byreducing or inhibiting tubulin polymerization or stability), or one ormore symptoms thereof, said method comprising: (a) administering to asubject in need thereof a dose of at least 150 μg/kg, preferably atleast 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg,at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or atleast 200 mg/kg or more of one or more compounds of the invention; and(b) administering one or more subsequent doses to said subject when themean absolute lymphocyte count in said subject is at least approximately500 cells/mm³, preferably at least approximately 600 cells/mm³, at leastapproximately 700 cells/mm³, at least approximately 750 cells/mm³, atleast approximately 800 cells/mm³, at least approximately 850 cells/mm³,or at least approximately 900 cells/mm³.

4.5 Biological Asssays

The anti-cancer activity of the pharmaceutical compositions andcompounds of the invention can be determined using any suitable animalmodel, including, but not limited to, SCID mice with a tumor or injectedwith malignant cells. Examples of animal models for lung cancer include,but are not limited to, lung cancer animal models described by Zhang &Roth (1994, In Vivo 8(5):755-69) and a transgenic mouse model withdisrupted p53 function (see, e.g., Morris et al., 1998, J La State MedSoc 150(4):179-85). An example of an animal model for breast cancerincludes, but is not limited to, a transgenic mouse that overexpressescyclin D1 (see, e.g., Hosokawa et al., 2001, Transgenic Res10(5):471-8). An example of an animal model for colon cancer includes,but is not limited to, a TCR b and p53 double knockout mouse (see, e.g.,Kado et al., 2001, Cancer Res 61(6):2395-8). Examples of animal modelsfor pancreatic cancer include, but are not limited to, a metastaticmodel of PancO2 murine pancreatic adenocarcinoma (see, e.g., Wang etal., 2001, Int J Pancreatol 29(1):37-46) and nu-nu mice generated insubcutaneous pancreatic tumors (see, e.g., Ghaneh et al., 2001, GeneTher 8(3):199-208). Examples of animal models for non-Hodgkin's lymphomainclude, but are not limited to, a severe combined immunodeficiency(“SCID”) mouse (see, e.g., Bryant et al., 2000, Lab Invest 80(4):553-73)and an IgHmu-HOX11 transgenic mouse (see, e.g., Hough et al., 1998, ProcNatl Acad Sci USA 95(23):13853-8). An example of an animal model foresophageal cancer includes, but is not limited to, a mouse transgenicfor the human papillomavirus type 16 E7 oncogene (see, e.g., Herber etal., 1996, J Virol 70(3):1873-81). Examples of animal models forcolorectal carcinomas include, but are not limited to, Apc mouse models(see, e.g., Fodde & Smits, 2001, Trends Mol Med 7(8):369-73 andKuraguchi et al., 2000, Oncogene 19(50):5755-63).

The anti-inflammatory activity of the pharmaceutical compositions andcompounds of the invention can be determined by using variousexperimental animal models of inflammatory arthritis known in the artand described in Crofford L. J. and Wilder R. L., “Arthritis andAutoimmunity in Animals”, in Arthritis and Allied Conditions: A Textbookof Rheumatology, McCarty et al.(eds.), Chapter 30 (Lee and Febiger,1993). Experimental and spontaneous animal models of inflammatoryarthritis and autoimmune rheumatic diseases can also be used to assessthe anti-inflammatory activity of the pharmaceutical compositions andcompounds of the invention. The following are illustrative assaysprovided as examples and not by limitation.

The principal animal models for arthritis or inflammatory disease knownin the art and widely used include: adjuvant-induced arthritis ratmodels, collagen-induced arthritis rat and mouse models andantigen-induced arthritis rat, rabbit and hamster models, all describedin Crofford L. J. and Wilder R. L., “Arthritis and Autoimmunity inAnimals”, in Arthritis and Allied Conditions: A Textbook ofRheumatology, McCarty et al.(eds.), Chapter 30 (Lee and Febiger, 1993),incorporated herein by reference in its entirety.

The anti-inflammatory activity of the pharmaceutical compositions andcompounds of the invention can be assessed using a carrageenan-inducedarthritis rat model. Carrageenan-induced arthritis has also been used inrabbit, dog and pig in studies of chronic arthritis or inflammation.Quantitative histomorphometric assessment is used to determinetherapeutic efficacy. The methods for using such a carrageenan-inducedarthritis model is described in Hansra P. et al., “Carrageenan-InducedArthritis in the Rat,” Inflammation, 24(2): 141-155, (2000). Alsocommonly used are zymosan-induced inflammation animal models as knownand described in the art.

The anti-inflammatory activity of the pharmaceutical compositions andcompounds of the invention can also be assessed by measuring theinhibition of carrageenan-induced paw edema in the rat, using amodification of the method described in Winter C. A. et al.,“Carrageenan-Induced Edema in Hind Paw of the Rat as an Assay forAnti-inflammatory Drugs” Proc. Soc. Exp. Biol Med. 111, 544-547, (1962).This assay has been used as a primary in vivo screen for theanti-inflammatory activity of most NSAIDs, and is considered predictiveof human efficacy. The anti-inflammatory activity of the testpharmaceutical composition or compound of the invention is expressed asthe percent inhibition of the increase in hind paw weight of the testgroup relative to the vehicle dosed control group.

In a specific embodiment of the invention where the experimental animalmodel used is adjuvant-induced arthritis rat model, body weight can bemeasured relative to a control group to determine the anti-inflammatoryactivity of the pharmaceutical compositions and compounds of theinvention. Alternatively, the efficacy of the pharmaceuticalcompositions and compounds of the invention can be assessed using assaysthat determine bone loss. Animal models such as ovariectomy-induced boneresorption mice, rat and rabbit models are known in the art forobtaining dynamic parameters for bone formation. Using methods such asthose described by Yositake et al. or Yamamoto et al., bone volume ismeasured in vivo by microcomputed tomography analysis and bonehistomorphometry analysis. Yoshitake et al., “Osteopontin-Deficient MiceAre Resistant to Ovariectomy-Induced Bone Resorption,” Proc. Natl. Acad.Sci. 96:8156-8160, (1999); Yamamoto et al., “The Integrin LigandEchistatin Prevents Bone Loss in Ovariectomized Mice and Rats,”Endocrinology 139(3):1411-1419, (1998), both incorporated herein byreference in their entirety.

Additionally, animal models for inflammatory bowel disease can also beused to assess the efficacy of the pharmaceutical compositions andcompounds of the invention (Kim et al., 1992, Scand. J. Gastroentrol.27:529-537; Strober, 1985, Dig. Dis. Sci. 30(12 Suppl):3S—IOS).Ulcerative colitis and Crohn's disease are human inflammatory boweldiseases that can be induced in animals. Sulfated polysaccharidesincluding, but not limited to amylopectin, carrageen, amylopectinsulfate, and dextran sulfate or chemical irritants including but notlimited to trinitrobenzenesulphonic acid (TNBS) and acetic acid can beadministered to animals orally to induce inflammatory bowel diseases.

Animal models for asthma can also be used to assess the efficacy of thepharmaceutical compositions and compounds of the invention. An exampleof one such model is the murine adoptive transfer model in whichaeroallergen provocation of TH1 or TH2 recipient mice results in THeffector cell migration to the airways and is associated with an intenseneutrophilic (TH1) and eosinophilic (TH2) lung mucosal inflammatoryresponse (Cohn et al., 1997, J. Exp. Med. 1861737-1747).

Animal models for psoriasis can also be used to assess the efficacy ofthe pharmaceutical compositions and compounds of the invention. Animalmodels for psoriasis have been developed (see, e.g., Schon, 1999, J.Invest. Dermatol. 112:405-410).

Further, any assays known to those skilled in the art can be used toevaluate the prophylactic and/or therapeutic utility of thepharmaceutical compositions and compounds of the invention for thedisorders disclosed herein.

The effect of the pharmaceutical compositions and compounds of theinvention on peripheral blood lymphocyte counts can bemonitored/assessed using standard techniques known to one of skill inthe art. Peripheral blood lymphocytes counts in a subject can bedetermined by, e.g., obtaining a sample of peripheral blood from saidsubject, separating the lymphocytes from other components of peripheralblood such as plasma using, e.g., Ficoll-Hypaque (Pharmacia) gradientcentrifugation, and counting the lymphocytes using trypan blue.Peripheral blood T-cell counts in subject can be determined by, e.g.,separating the lymphocytes from other components of peripheral bloodsuch as plasma using, e.g., a use of Ficoll-Hypaque (Pharmacia) gradientcentrifugation, labeling the T-cells with an antibody directed to aT-cell antigen such as CD3, CD4, and CD8 which is conjugated to FITC orphycoerythrin, and measuring the number of T-cells by FACS.

The toxicity and/or efficacy of the pharmaceutical compositions andcompounds of the invention can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex and it can be expressed as the ratio LD₅O/ED₅₀. Pharmaceuticalcompositions and compounds of the invention that exhibit largetherapeutic indices are preferred. While pharmaceutical compositions andcompounds of the invention that exhibit toxic side effects may be used,care should be taken to design a delivery system that targets suchcompositions and compounds to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage of the pharmaceutical compositionsand compounds of the invention for use in humans. The dosage of suchagents lies preferably within a range of circulating concentrations thatinclude the ED₅₀ with little or no toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized. For any agent used in the method of theinvention, the therapeutically effective dose can be estimated initiallyfrom cell culture assays. A dose may be formulated in animal models toachieve a circulating plasma concentration range that includes the IC₅₀(i.e., the concentration of the test compound that achieves ahalf-maximal inhibition of symptoms) as determined in cell culture. Suchinformation can be used to more accurately determine useful doses inhumans. Levels in plasma may be measured, for example, by highperformance liquid chromatography (HPLC) and radioimmunoassay (RIA). Thepharmacokinetics of a prophylactic or therapeutic can be determined,e.g., by measuring parameters such as peak plasma level (C_(max)), areaunder the curve (AUC, which is measured by plotting plasma concentrationof the agent versus time, and reflects bioavailability), half-life ofthe compound (t_(1/2)), and time at maximum concentration.

Efficacy in preventing or treating a proliferative disorder such ascancer may be demonstrated, e.g., by detecting the ability of thepharmaceutical compositions and compounds of the invention to reduce oneor more symptoms of the proliferative disorder, to reduce theproliferation of cancerous cells, to reduce the spread of cancerouscells, or to reduce the size of a tumor. Efficacy in preventing ortreating an inflammatory disorder may be demonstrated, e.g., bydetecting the ability of the pharmaceutical compositions and compoundsof the invention to reduce one or more symptoms of the inflammatorydisorder, to decrease T cell activation, to decrease T cellproliferation, to modulate one or more cytokine profiles, to reducecytokine production, to reduce inflammation of a joint, organ or tissueor to improve quality of life. Changes in inflammatory disease activitymay be assessed through tender and swollen joint counts, patient andphysician global scores for pain and disease activity, and the ESR/CRP.Progression of structural joint damage may be assessed by quantitativescoring of X-rays of hands, wrists, and feet (Sharp method). Changes infunctional status in humans with inflammatory disorders may be evaluatedusing the Health Assessment Questionnaire (HAQ), and quality of lifechanges are assessed with the SF-36.

4.6 EXAMPLES

4.6.1 Biological Assays

Compounds of the invention can be assayed using the examples set forthbelow. General chemicals, as well as tubulin inhibitors Taxol,vinblastine, and colchicine can be purchased from Sigma (St. Louis,Mo.). All compounds are dissolved in 100% DMSO before further dilutionin cell culture media. Final DMSO concentrations are kept at a constant0.1% for all samples, including controls, unless otherwise stated.Streptavidin-coated yttrium SPA beads are obtained from AmershamPharmacia Biotech (Piscataway, N.J.). [³H]colchicine is available fromNew England Nuclear (Boston, Mass.), and [³H]Taxol and [³H]vinblastinewere from Morevek Biochemicals (Brea, Calif.). Purified tubulin andbiotinylated microtubule associated protein-free bovine brain tubulinare available from Cytoskeleton, Inc. (Denver, Colo.).

The human tumor cell lines HT29 (colon adenocarcinoma, HTB-38), HT-144(melanoma, HTB-63), HCT 116 (colorectal carcinoma, CCL-247), A549(NSCLC, CCL 185), NIH:OVCAR-3 (ovary adenocarcinoma, HTB-161), PC-3(prostate adenocarcinoma, CRL-1435), HCT-15 (colorectal adenocarcinoma,CCL-225), MCF-7 (breast adenocarcinoma, HTB-22), MES-SA (uterinesarcoma, CRL-1976), MES-SA/MX2 (CRL-2274), MES-SA/Dx5 (CRL-1977), areavailable from American Type Culture Collection (Manassas, Va.).MCF-7/ADR is provided by the Signal Research Division of CelgeneCorporation. All cell lines are cultivated at 37° C., 5% CO₂ in mediumas published or as stated on ATCC information sheets. The detailedcharacteristics of human parental MCF-7, MES-SA cell lines as well asthe multidrug-resistant, P-gp 170-overexpressing MCF-7/ADR, MES-SA/MX2,MES-SA/Dx5, HCT-15 cell lines have been reported (see Shan, J., Mason,J. M., Yuan, L., Barcia, M., Porti, D., Calabro, A., Budman, D.,Vinciguerra, V., and Xu, H. Rab6c, “A new member of the rab gene family,is involved in drug resistance in MCF7/AdrR cells”, Gene 257:67-75(2000)). HUVEC is provided by the Cellular Therapeutic Division ofCelgene Corporation. PBMC from normal donors is obtained byFicoll-Hypaque (Pharmacia, Piscataway, N.J.) density centriftigation.

4.6.1.1 Cell Proliferation Assay

Cell proliferation is assessed in cancer cell lines, HUVEC and humanPBMC by [³H]thymidine incorporation assay. Briefly, cells are seeded on96-well microtiter plates 24 hours before addition of compound to allowthem to adhere to plates. Each compound is tested at serial dilutions intriplicate. Following compound treatment, the cells are incubated at 37°C. for additional 72 hours. [³H]thymidine (1 μCi in 20 μl medium) isadded to each well for the last 6 hours of incubation time. The cellsare then harvested for detection of tritium incorporation with aTopCount® Microplate Scintillation Counter (Packard Instrument Company,Meriden, Conn.). IC₅₀ is calculated from nonlinear regression analysisusing GraphPad Prism® program (San Diego, Calif.).

4.6.1.2 Flow Cytometric Analysis

For cell cycle analysis, cells are harvested following treatment withtest agents for 24 h, and stained with propidium iodide (PI), perinstruction of Cycle Test Plus DNA Reagent Kits from Becton Dickinson(San Jose, Calif.). Samples are examined using FACS Calibur instrument(Becton Dickinson, San Jose, Calif.). Cell cycle distribution isanalyzed with CellQuest™ v3.1 acquisition software and the ModFit™ v2.0program.

For apoptosis analysis, cells are treated with test agents for 48 h andthen harvested. Double staining for FITC-Annexin V binding and for DNAusing PI is performed as described before (see Zhang, L. H. and Longley,R. E., “Induction of apoptosis in mouse thymocytes by microcolin A andits synthetic analog”, Life Sci, 64:1013-1028 (1999)).

4.6.1.3 Tubulin Polymerization or stability Assay

The polymerization or stability of purified tubulin is monitored usingthe CytoDYNAMIX™ Screen (Cytoskeleton, Denver, Colo.). This assay uses a96-well assay plate format with 200 μg of lyophilized purified tubulinin each well. The tubulin is reconstituted with ice-cold 180 μlpolymerization or stability buffer (80 mM PIPES, 1 mM MgCl₂, 1 mM EGTA)containing test compounds, or vehicle control DMSO. The assay isconducted at 37° C. in a temperature-controlled microtiter plate reader.Tubulin polymerization or stability is monitored spectrophotometricallyby the change in absorbance at 340 nm. The absorbance is measured at1-min intervals for 60 min, using a PowerWave™ HT microplate reader(Bio-Tek Instruments, Highland Park, Vt.).

4.6.1.4 Immunofluorescence Microscopy

Detection of α-tubulin in A549 cells by immunofluorescence is done asdescribed before (see Isbrucker, R. A., Gunasekera, S. P., and Longley,R. E, “Structure-activity relationship studies of discodermolide and itssemisynthetic acetylated analogs on microtubule function andcytotoxicity”, Cancer Chemother. Pharmacol., 48:29-36 (2001)). Briefly,cells are treated with test compounds for 24 h, washed with PBS. Cellsare then fixed and permeabilized with warm PBS buffer containing 3.7%formaldehyde and 1% Triton-X for 30 min. After washing cells twice withPBS and saturation with 1% mouse blocking serum in PBS for 30 min,staining is performed with an anti-α-tubulin-FITC antibody (Sigma) aloneor in the presence of 100 μg/ml of propidium iodide. Cells are observedunder an epifluorescence microscope (Nikon Instruments, Melville, N.Y.)and imaged with a CCD camera using Image-Pro™ (Media Cybernetics, SilverSpring, Md.).

4.6.1.5 Tubulin Competition-Binding SPA Assay

The tubulin-binding assay is performed as previously reported (seeTahir, S. K., Kovar, P., Rosenberg, S. H., and Ng, S.C., “Rapidcolchicine competition-binding scintillation proximity assay usingbiotin-labeled tubulin”, Biotechniques, 29:156-160 (2000)) usingbiotin-labeled tubulin, streptavidin-coated yttrium SPA beads, and[³H]-labeled ligands ([³H]colchicine, [³H]Taxol, or [³H]vinblastine).Briefly, the binding mixture includes 0.08 μM [³H]-labeled ligand, 1 mMGTP, and 0.5 μg of biotinylated tubulin in 100-μl of assay buffercontaining 80 mM PIPES pH 6.9, 1 mM MgCl₂, 1 mM EGTA, and 5% glycerol.The test compound and [³H]-labeled ligand are added before tubulin.After incubation at 37° C. for 2 h, 20 μl of SPA beads (80 μg in theassay buffer) are added. After further incubation for 30 min underagitation at room temperature, the SPA beads are allowed to settle downfor 45 min, and scintillation counting is done on the TopCount®Microplate Scintillation Counter.

4.6.1.6 Caspase Assay

Caspase activity is determined per instructions from the assay kitsupplier (R&D systems, Minneapolis, Minn.). Briefly, cells are collectedand centrifuged at 250×g for 10 minutes, following drug treatment. Cellpellets are lysed using lysis buffer. Cell lysates are incubated on icefor 10 minutes and then centrifuged at 10,000×g for 1 minute. Theenzymatic reaction for caspase activity is carried out in 96 wellmicrotiter plates. 50 μl of lysate containing 200 μg of total protein,50 μl of 2× reaction buffer and 5 μl of caspase specific peptidesubstrates (DEVD, IETD or LEHD conjugated to p-nitroanaline forcaspase-3, -8. -9 respectively) are mixed. The mixtures are incubated at37° C. for 2 hours before A_(405nm) is read using the microplate reader.The results are expressed as fold change in caspase activity ofdrug-treated cells over the vehicle control cells.

4.6.1.7 Immunoblot Analysis of Cell Cycle Regulatory Proteins

Cancer cells are treated with a compound of the invention or 0.1% DMSOfor 24 h. Cells are trypsinized and spun down for 6 seconds in amicrofuge and immediately lysed in 0.1 ml lysis buffer containing 10 mMTris-HCl pH 8.0, 10 mM EDTA, 150 mM NaCl, 1% NP-40, 0.5% SDS, 1 mM DTT,1 mM Na₃VO₄, plus Complete protease inhibitor cocktail (Roche AppliedScience, Indianapolis, Ind.), then spun through a Qiashredder™ (Qiagen,Valencia, Calif.) for 1 minute and frozen on dry ice. Samples arediluted with 3×SDS sample buffer (New England Biolabs, Beverly, Mass.)and boiled 5 minutes. Approximately 30 μl of this mixture is loaded perlane on Tris-Glycine polyacrylamide gels (Invitrogen, Carlsbad, Calif.),electrophoresed, and transferred to PVDF membranes (Invitrogen). PVDFmembranes are blocked for 1 hour at room temperature in PBS containing0.05% Tween-20 and 5% non-fat milk powder, then blotted overnight at 4°C. with antibodies against either MPM-2 (Upstate Biotechnology, LakePlacid, N.Y.), Bcl-2, Cdc2, p53, p21 or Cdc25C (Santa CruzBiotechnology, Santa Cruz, Calif.). Membranes are washed and incubatedwith HRPO conjugated anti-rabbit or anti-mouse IgG (Santa CruzBiotechnology, Santa Cruz, Calif.) (1:10,00 dilution) for 60 minutes atroom temperature, washed 3 times, then developed using the ECL Pluschemiluminescent detection system (Amersham Biosciences, Piscataway,N.J.).

4.6.1.8 PBMC Culture and ELISA for TNF-α

PBMC are prepared by density centrifugation on Ficoll-Hypaque. PBMC,re-suspended at 1×10⁶/ml in complete RPMI-1640 medium/10% fetal calfserum, are stimulated with LPS (1 μg/ml; Escherichia coli serotype0127:B8; Sigma) in 24-well plates by incubation at 37° C. in 5% CO₂ for24 h±compounds (0.1-100 μM). Cell-free supernatants are collected andstored in aliquots at −70° C. until assayed by ELISA. Supernatants areassayed for TNF-α using an assay procedure and reagents provided by R&DSystems (Minneapolis, Minn.).

4.6.1.9 PDE4 Assay

PDE purification from U937 cells is performed as described previously(see Marriott, J. B., Westby, M., Cookson, S., Guckian, M., Goodboum,S., Muller, G., Shire, M. G., Stirling, D., and Dalgleish, A. G.,“CC-3052: A water-soluble analog of thalidomide and potent inhibitor ofactivation-induced TNF-alpha production”, J. Immunol., 161:4236-4243(1998)). Briefly, cells (1×10⁹) are washed in PBS and lysed in coldhomogenization buffer (20 mM Tris-HCl, pH 7.1, 3 mM 2-mercaptoenthanol,1 mM MgCl₂, 0.1 mM EGTA, 1 μM PMSF, 1 μg/ml leupeptin). Followinghomogenization, the supernatant is collected by centrifugation andloaded onto a Sephacryl S-200 column equilibrated in homogenizationbuffer. PDE is eluted in homogenization buffer and rolipram-sensitivefractions pooled and stored in aliquots. PDE activity is assayed by aprocedure described by Di Santo and Heaslip (DiSanto, M. E. and Heaslip,R. J., “Identification and stabilization of large molecular weightPDE-IVs from U937 cells”, Biochem. Biophys. Res. Commun., 197:1126-1131(1993)) and in the presence of varying concentrations of compounds, 50mM Tris-HCl, pH 7.5, 5 mM MgCl₂, and 1 μM cAMP (of which 1% was[³H]cAMP). The amount of extract used is predetermined to ensure thatreactions are within the linear range and consumed <15% of the totalsubstrate. Reactions are performed at 30° C. for 30 min and terminatedby boiling for 2 min. The samples are then chilled and treated withsnake venom (1 mg/ml) at 30° C. for 15 min. Unused substrate is removedby addition of 200 μl AG1-X8 resin (Bio-Rad, Richmond, Calif.) for 15min. Samples are then spun at 3000 rpm for 5 min, and 50 μl of theaqueous phase is taken for counting. Each data point is conducted induplicate with activity expressed as percentage of control. IC₅₀ isdetermined from dose-response curves derived from three independentexperiments.

4.6.1.10 Human Tumor Xenograft Model

CB17 SCID mice (6-8 weeks old, female) are maintained in microisolatorcages under sterile conditions. HCT-116 (colon cancer) cells suspendedin sterile PBS are injected subcutaneously into mice (2×10⁶cells/mouse). On day 6, tumors of all mice are measured with a digitalcaliper and volumes calculated with a formula of W²×L/2 [W=width (shortaxis); L=Length (long axis)]. Mice bearing tumor size ranging between75-125 mm³ are pooled together and randomly distributed into cages. Themice are then ear tagged and cages were randomly assigned to treatmentgroups. On day 7, the tumors are measured and considered as startingvolumes, the mice are then administered i.p. with either vehicle control(N-methyl-2 pyrrolidone: PEG400: saline at ratio of 1:9:10), CC-5079 (5and 25 mg/kg) or positive control Camptosar™ (10 mg/kg). Tumor sizes aredetermined at intervals indicated.

4.6.1.11 Cell Adhesion Assay

HUVECs are seeded on 24 well culture plates and incubated for 2 days toallow formation of a confluent monolayer. Cancerous cells or a cancercell line such as LS-180 human colon adenocarcinoma cells are labeledwith 5 μM Calcein-AM for 30 min. Calcein-AM labeled LS-180 cells areadded into each well of the HUVEC culture and incubated for 10 min at37° C. TNF-α (80 ng/ml) is then added and the culture is incubated foran additional 110 min. Non-adherent cells are removed by washing withPBS. The fluorescence intensity of adherent LS-180 cell in eachindividual well is measured by a fluorescent plate reader set atexcitation 485/20 nm and emission at 530/25 nm.

4.6.1.12 Cell Migration and Invasion Assay

Cell migration and invasion are determined using an assay based on theBD BioCoast Angiogenesis System (BD Biosciences, Bedford, Mass.). Thefluorescence blocking membrane of the insert is a 3 micron pore size PETfilter which has been coated either with BD Matrigel basement matrix(for invasion assay) or without Matrigel matrix (for migration assay).HUVECs (250 μl/well) in culture medium without serum are added to thetop chamber and a compound of the invention is added to bottom wellscontaining medium (750 μl/well) with VEGF as a chemo-attractant. Cellsare then incubated for 22 h at 37° C. After incubation, cells arestained with Calcein AM for measurement of fluorescence.

4.6.1.13 Aniiogenesis Assay

The effect of a compound of the invention on angiogenesis is assessedusing fresh human umbilical cords collected by trained medicalpersonnel. The cords are transported directly to the laboratory withinabout three hours and umbilical cords and vessel lumens are rinsed withchilled basal nutrient medium. The artery is removed from the cord usingmechanical means, forceps and small surgical scissors in an asepticfield. The vessel is cleaned of connective tissue and vessel rings arecut cross-wise in a length of 1 mm. The rings are placed into EGM-2medium (Clonetics Corp), in a 50 ml conical bottom tube and transportedat 4° C. to Celgene corporation. Six-well tissue culture plates arecovered with 250 μl of Matrigel and allowed to gel for 30-45 min at 37°C., 5% CO₂. The vessel rings are rinsed in EGM-w medium and placed onthe Matrigel coated wells, covered with additional 250 μl Matrigel, andallowed to gel for 30-45 min at 37° C. The vessels are cultured for 24hours in 4 ml of EGM-2 to allow the tissue to adapt to its newenvironment. After 24 hours incubation, the rings are treated eitherwith 0.1% DMSO as control, or different concentrations of a compound ofthe invention. Culture medium is changed twice per week for total ofthree weeks. The effects of the compound of the invention are comparedwith DMSO treated vessel rings. The results are analyzed usingimage-proplus software.

4.6.2 Synthesis of Illustrative Compounds of the Invention 4.6.2.13-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

A solution of 6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.09 g, 5.07 mmol)in anhydrous THF (10 ml) was cooled to −78° C., evacuated and refilledwith nitrogen for ten cycles. To this clear solution was slowly addedn-butyl lithium (2.03 ml, 5.07 mmol) and stirred for 30 min. Then asolution of 3,5-dimethoxybenzaldehyde (0.77 g, 4.61 mmol) in anhydrousTHF (10 ml) was added via a syringe. The mixture was stirred at −78° C.under nitrogen for 4 h then quenched with 2-propanol (2.10 ml, 27.65mmol) and stirred overnight. To the orange colored mixture was added 30ml of water and extracted with ether (3×60 ml). The combined etherextracts was washed with water (2×60 ml), dried over MgSO₄, filtered andconcentrated in vacuo to an oil, which was purified via flash columnchromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane inabout 40 min.) to give(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanol as alight brown oil (1.27 g, 91%), HPLC purity was 93.4% at 3.45 min. (50/50ACN/0.1% H₃PO₄): ¹HNMR (CDCl₃) δ 6.88-6.79 (m, 3H, Ar), 6.54 (d, J=2 Hz,2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.65 (d, J=3 Hz, 1H, CH), 4.22 (m,4H, 2CH₂), 3.77 (s, 6H, OCH₃), 2.25 (d, J=3 Hz, 1H, OH). The product wascarried over to the next step.

To a stirred solution of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)-methanol (1.15g, 3.80 mmol) in CH₂Cl₂ (20 ml) at rt was added activated MnO₂ powder(1.65 g, 19 mmol) and kept adding 23 equivalents of MnO₂ every 35 huntil HPLC showed at least 98% conversion occurred. The black suspensionwas filtered through a Celite pad, concentrated in vacuo to give(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanone asan oil (1.06 g, 93%): ¹HNMR (CDCl₃) δ 7.42 (d, J=1 Hz, 1H, Ar), 7.38(dd, J=1.88, 8 Hz, 1H, Ar), 6.92 (d, J=8 Hz, 1H, Ar), 6.88 (d, J=2 Hz,2H, Ar), 6.64 (t, J=2 Hz, 1H, Ar), 4.36-4.29 (m, 4H, 2CH₂), 3.82 (s, 6H,OCH₃). The product was carried over to the next step.

To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.08ml, 6.86 mmol) in anhydrous THF (10 ml) in an ice bath was added lithiumbis-(trimethylsilyl)amide (1.0 M solution in THF, 6.86 ml, 6.86 mmol)slowly. The mixture was stirred at rt for 40 min, before a solution of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone (1.03g, 3.43 mmol) in anhydrous THF (20 ml) was added. The mixture wasrefluxed overnight. The solution was poured into ice water (20 ml) andthe two phases were separated. The THF phase was evaporated and combinedwith the aqueous phase, which were then extracted with CH₂Cl₂ (2×40 ml),washed with water (50 ml), dried over MgSO₄, filtered and concentratedin vacuo to an oil, which was purified via flash column chromatography5% EtOAc in hexane gradient to 25% EtOAc in hexane) to give3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrileas an oil (0.98 g, 88%): ¹H NMR (DMSO-d₆) δ 6.99-6.79 (m, 3H, Ar),6.65-6.62 (2ts, 1H, Ar), 6.46-6.44 (2ds, 2H, Ar), 6.25 (s, 0.47H, doublebond proton of one isomer), 6.20 (s, 0.54H, double bond proton of theother isomer), 4.33-4.24 (m, 4H, 2CH₂), 3.76 (s, 3H, OCH₃), 3.74 (s, 3H,OCH₃); ¹³C NMR (DMSO-d₆) δ 179.5, 160.8, 160.7, 145.7, 144.8, 143.3,143.0, 140.3, 139.1, 130.4, 129.7, 122.5, 121.7, 118.2, 118.1, 117.9,117.2, 117.1, 116.6, 107.1, 106.7, 101.8, 100.9, 95.4, 94.3, 64.4, 64.2,64.0, 64.0, 55.4, 54.9; Anal. Calcd. For C₁₉H₁₇NO₄ (+0.05H₂O): C, 69.40;H, 5.26; N, 4.24. Found: C, 69.19; H, 5.11; N, 4.25.

4.6.2.2 2E and 2Z3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

About 0.7 g of oily3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrilewas purified via Prep HPLC using 40% acetonitrile/60% water (90 min.run) to give 2E and 2Z isomers (about 200 mg white solid each isomer).

2E3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile:HPLC purity was 98.03% at 4.76 min (60/40 ACN/H₂O). mp, 93-95° C.; ¹HNMR(DMSO-d₆) δ 6.93 (d, J=2 Hz, 1H, Ar), 6.89 (d, J=8 Hz, 1H, Ar), 6.81(dd, J=1.95, 8 Hz, 1H, Ar), 6.64 (t, J=2 Hz, 1H, Ar), 6.44 (d, J=2 Hz,2H, Ar), 6.24 (s, 1H, double bond proton), 4.29-4.24 (m, 4H, CH₂), 3.76(s, 6H, OCH₃); ¹³C NMR (DMSO-d₆) δ 160.7, 160.4, 145.7, 143.3, 139.1,130.4, 121.7, 118.2, 117.2, 116.6, 107.1, 100.9, 94.3, 64.4, 64.0, 55.4;Anal. Calcd. for C₁₉H₁₇NO₄ (+0.05H₂O): C, 70.38; H, 5.32; N, 4.32.Found: C, 70.12; H, 5.29; N, 4.36. The absolute structure was determinedvia NOE.

2Z3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile:HPLC purity was 97.39% at 5.22 min (60/40 ACN/H₂O). mp, 100-102° C.;¹HNMR (DMSO-d₆) δ 6.97 (d, J=8 Hz, 1H, Ar), 6.89 (d, J=1 Hz, 1H, Ar),6.82 (dd, J=2.09, 8 Hz, 1H, Ar), 6.62 (t, J=2 Hz, 1H, Ar), 6.45 (d, J=2Hz, 2H, Ar), 6.20 (s, 1H, double bond H), 4.33-4.28 (m, 4H, CH₂), 3.73(s, 6H, OCH₃); ¹³C NMR (DMSO-d₆) δ 160.8, 160.4, 144.8, 143.0, 140.3,129.7, 122.6, 118.2, 117.9, 117.1, 106.8, 101.8, 95.5, 64.3, 64.0, 55.4;

Anal. Calcd. for C₁₉H₁₇NO₄ (+0.25H₂O): C, 69.61; H, 5.38; N, 4.27;Found: C, 69.64; H, 5.40; N, 4.42. The absolute structure was determinedvia NOE.

4.6.2.33-(3,5-Dimethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile

Ethyldiisopropylamine (1.72 ml, 9.85 mmol) was added to a solution of5-bromo-2-methoxy-phenol (0.80 g, 3.94 mmol) in DMF (10 ml) at rt. Theclear, colorless solution was stirred for 5 min. followed by addition oftert-butylchlorodimethylsilane (0.71 g, 4.73 mmol). The reaction wascomplete in about two hours. Distilled water (6 ml) was added to theclear solution, stirred for 10 min., added ether (50 ml) and sat. NaHCO₃(10 ml), stirred for 30 min. The ether portion was separated and theaqueous phase was extracted with ether (2×50 ml). The combined etherphases were washed with water (100 ml), brine (60 ml), dried over MgSO₄,filtered and concentrated to an oil, which was further purified by flashcolumn chromatography [100% hexane with 0.5% triethylamine gradient to30% EtOAc in hexane with 0.5% Et₃N] to give(5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane as an oil (0.59g, 99%), HPLC purity 99.5% at 1.43 min. (90/10 ACN/0.1% H₃PO₄): ¹H NMR(DMSO-d₆) δ 7.04-6.97(m, 2H, Ar), 6.71 (d, J=8 Hz, Ar), 3.78 (s, 3H,single OCH₃), 0.99 (s, 9H, 30CH₃), 0.16 (s, 6H, 20CH₃). The product wascarried over to the next step.

(5-Bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (0.98 g, 3.09 mmol),n-butyl lithium (1.24 ml, 3.09 mmol), and 3,5-dimethoxybenzaldehyde(0.47 g, 2.81 mmol) were treated in the same manner as described abovefor the synthesis of (2,3-drihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material waspurified via flash column chromatography (5% EtOAc in hexane gradient to30% EtOAc in hexane in about 40 min.) to give[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanolas an oil (0.79 g, 69%), HPLC purity was 98.3% at 2.55 min. (90/10ACN/0.1% H₃PO₄): ¹HNMR (CDCl₃) δ 6.92-6.78 (m, 3H, Ar), 6.53 (d, J=2 Hz,2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.66 (d, J=3 Hz, 1H, CH), 3.78 (s,3H, single OCH₃), 3.76 (s, 6H, 2OCH₃), 2.15 (d, J=3 Hz, 1H, OH), 0.97(s, 9H, 30CH₃), 0.13 (s, 6H, 20CH₃). The product was carried over to thenext step.

[3-(tert-Butyldimethylsilanyloxy)-4-methoxyphenyl]-(3,5-dimethoxyphenyl)methanol(0.78 g, 1.93 mmol) and activated MnO2 powder (1.33 g, 15 mmol) weretreated in the same manner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanonewas an oil (0.82 g, 100%): ¹HNMR (CDCl₃)

7.47-7.40 (m, 2H, Ar), 6.90-6.86 (m, 3H, Ar), 6.65 (t, J=2 Hz, 1H, Ar),3.88 (s, 3H, OCH3), 3.82 (s, 6H, 20CH3), 0.99 (s, 9H, 30CH3), 0.18 (s,6H, 20CH3). The product was carried over to the next step.

[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(3,5-dimethoxyphenyl)methanone (0.74 g, 1.84 mmol), cyanomethylphosphonic acid diethyl ester(0.58 ml, 3.68 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 3.70 ml, 3.68 mmol) weretreated in the same manner as described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)-acrylonitrile.The crude was purified via flash column chromatography (100% hexanegradient to 20% EtOAc in hexane in about 40 min.) to give3-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrileas an clear colorless oil (0.58 g, 74%): ¹HNMR (CDCl₃) δ 7.09-6.78 (m,3H, Ar), 6.53-6.51 (m, 2H, Ar), 6.41 (d, J=2 Hz, 1H, Ar), 5.60 (s, 1H,Ch), 3.86-3.76 (multiple singlets, 9H), 0.97 (s, 9H, 30CH₃), 0.14 (s,6H, 20CH₃). The product was carried over to the next step.

Tetrabutylammonium fluoride (1.0 M solution in THF, 1.49 ml, 1.49 mmol)was added at rt to a stirred solution of3-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-3-(3,5-dimethoxyphenyl)acrylonitrile(0.53 g, 1.25 mmol) in THF (15 ml). The colorless clear solutionimmediately turned into brown/red wine color. The reaction should bedone within one hour. Ice water (10 ml) was poured into the reddishsolution, followed by addition of ether (50 ml). The mixture was washedwith water (2×80 ml), dried over MgSO₄, filtered and concentrated to ayellow oil, which was lyophilized to give3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile asa foamy solid (0.35 g, 90%): mp, 43-45° C.; ¹HNMR (DMSO-d₆) δ 9.36 (s,1H, OH group of one isomer), 9.28 (s, 1H, OH group of the other isomer),7.07 (d, J=8 Hz, 1H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 6.91-6.82 (m, 4H,Ar), 6.69-6.65 (m, 2H, Ar), 6.49 (t, J=2 Hz, 4H, Ar), 6.19 (s, 1H,double bond proton of one isomer), 6.17 (s, 1H, double bond proton ofthe other isomer), 3.87 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 3.81 (s, 6H,20CH₃), 3.78 (s, 6H, 20CH₃), isomer ratio based on ¹HNMR was 45%: 55%;¹³C NMR (CDCl₃) δ 162.8, 162.6, 160.8, 160.8, 148.7, 148.2, 145.7,145.5, 141.4, 139.1, 131.9, 130.2, 122.3, 121.3, 118.2, 118.1, 116.0,114.4, 110.4, 110.4, 107.8, 107.1, 102.2, 94.2, 93.5, 56.2, 56.1, 55.6;Anal. Calcd. For C₁₈H₁₇NO₄: C, 69.12; H, 5.53; N, 4.48. Found: C, 68.76;H, 5.69; N, 4.22.

4.6.2.4 3-Benzo[1,3]dioxol-5-yl-3-(3,5-dimethoxy-phenyl)-acrylonitrile

1-Bromo-3,5-dimethoxybenzene (0.47 g, 3.14 mmol),benzo[1,3]dioxole-5-carbaldehyde (0.75 g, 3.46 mmol), and n-butyllithium (1.38 ml, 3.46 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude was purified via flash column chromatography (5% EtOAc in hexanegradient to 30% EtOAc in hexane in about 40 min.) to giveBenzo[1,3]dioxol-5-yl-(3,5-dimethoxy-phenyl)-methanol as an off-whiteoil (0.73 g, 81%): ¹HNMR (CDCl₃)

6.87-6.83 (m, 2H, Ar), 6.77-6.74 (m, 1H, Ar), 6.53 (d, J=2 Hz, 2H, Ar),6.36 (t, J=2 Hz, 1H), 5.93 (m, 2H, CH₂), 5.68 (d, J=3 Hz, 1H, CHOH),3.77 (s, 6H, 20CH₃), 2.15 (d, J=3 Hz, 1H, OH). The product was carriedover to the next step.

Benzo[1,3]dioxol-5-yl-(3,5-dimethoxyphenyl)methanol (0.72 g, 2.43 mmol)and activated MnO₂ powder (3.4 g, 39 mmol) were treated in the samemanner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl) methanone. Theproduct benzo[1,3]dioxol-5-yl-(3,5-dimethoxy-phenyl)-methanone was anoff-white solid (0.64 g, 92%): ¹HNMR (CDCl₃)

7.43-7.38 (m, 2H, Ar), 6.88-6.84 (m, 3H, Ar), 6.65 (t, J=2 Hz, 1H, Ar),6.07 (s, 2H, CH₂), 3.83 (s, 6H, 20CH₃). The product was carried over tothe next step.

Benzo[1,3]dioxol-5-yl-(3,5-dimethoxyphenyl)methanone (0.63 g, 2.20mmol), cyanomethylphosphonic acid diethyl ester (0.69 ml, 4.40 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 4.40 ml, 4.40 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo-[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) togive a light brown oil, which was lyophilized to givebenzo[1,3]dioxol-5-yl-(3,5-dimethoxy-phenyl)-methanone as a solid (0.64g, 94%): mp, 147-149° C.; ¹HNMR (DMSO-d₆) δ 7.11 (d, J=1 Hz, 1H, Ar),7.04 (d, J=7 Hz, 1H, Ar), 6.95-6.92 (m, 2H, Ar), 6.87 (dd, J=1.7, 7 Hz,1H, Ar), 6.73 (dd, J=1 Hz and 8 Hz, 1H, Ar), 6.65-6.62 (m, 2H, Ar),6.47-6.45 (m, 4H, Ar), 6.25 (s, 1H, double bond proton of one isomer),6.24 (s, 1H, double bond proton of the other isomer), 6.12 (s, 2H, CH₂of one isomer), 6.09 (s, 2H, CH₂ of the other isomer), 3.76 (s, 3H,OCH₃), 3.73 (s, 3H, OCH₃), isomer ratio based on ¹HNMR was 44%: 56%; ¹³CNMR (DMSO-d₆) δ 161.1, 160.9, 160.4, 149.4, 148.5, 147.9, 147.3, 140.2,139.2, 131.4, 130.5, 123.8, 123.7, 118.2, 118.2, 109.3, 108.3, 108.2,107.3, 107.1, 106.7, 101.9, 101.8, 101.7, 10.0, 95.8, 94.4, 55.4, 55.4;Anal. Calcd. For C₁₈H₁₅NO₄: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.90;H, 4.70; N, 4.52.

4.6.2.5 3,3-Bis-(3,5-dimethoxy-phenyl) acrylonitrile

3,5-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol),1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium(2.20 ml, 5.53 mmol) were treated in the same manner as described abovefor the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material waspurified via flash column chromatography (10% EtOAc in hexane gradientto 60% EtOAc in hexane in about 40 min.) to giveBis-(3,5-dimethoxy-phenyl)-methanol as an off-white solid (1.31 g, 86%):¹HNMR (CDCl₃) δ 6.55 (d, J=2 Hz, 4H, Ar), 6.36 (t, J=2 Hz, 2H, Ar), 5.67(d, J=3 Hz, 1H, CHOH), 3.77 (s, 12H, 40CH₃), 2.24 (d, J=3 Hz, 1H, OH).The product was carried over to the next step.

Bis-(3,5-dimethoxyphenyl)methanol (1.30 g, 4.27 mmol) and activated MnO₂powder (1.86 g, 21 mmol) were treated in the same manner as describedabove for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct bis-(3,5-dimethoxy-phenyl)methanone was an off-white solid (1.36g, 100%): ¹HNMR (CDCl₃) δ 6.93 (d, J=2 Hz, 4H, Ar), 6.67 (t, J=2 Hz, 2H,Ar), 3.83 (s, 12H, 40CH₃). The product was carried over to the nextstep.

Bis-(3,5-dimethoxyphenyl)methanone (1.29 g, 4.27 mmol),cyanomethylphosphonic acid diethyl ester (1.34 ml, 8.53 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 8.53 ml, 8.53 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 40% EtOAc in hexane in about 45 min.) togive 3,3-bis-(3,5-dimethoxy-phenyl)-acrylonitrile as an off-white solid(1.06 g, 76%): mp, 149-151° C.; ¹HNMR (DMSO-d₆) δ 6.66-6.62 (m, 2H, Ar),6.50-6.47 (m, 4H, Ar), 6.39 (s, 1H, double bond proton), 3.76 (s, 6H,20CH₃), 3.74 (s, 6H, 20CH₃); ¹³CNMR(CDCl₃)δ 163.0, 160.9, 160.8, 140.8,138.7, 117.7, 107.8, 106.9, 102.4, 102.2, 95.5, 55.6; Anal. Calcd. ForC₁₉H₁₉NO₄: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.93; H, 5.96;N,4.18.

4.6.2.6 3-(2,5-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

Aluminum chloride (3.76 g, 28.18 mmol) was added to a stirred mixture of1,3-dimethoxybenzene (3.54 g, 25.62 mmol) in anhydrous methylenechloride (20 ml) in an ice bath. A solution of 3,5-dimethoxybenzoylchloride (5.14 g, 25.62 mmol) in anhydrous methylene chloride (50 ml)was then added. The mixture was allowed to warm up to rt and refluxedovernight. After cooling down to rt, the mixture was poured to ice water(50 ml), stirred for 20 min., and extracted with methylene chloride(3×50 ml). The combined organic extracts was washed with sat. NaHCO₃(3×50 ml), H₂O (2×50 ml), brine (50 ml), dried over MgSO₄, filtered andconcentrated in vacuo to an oil, which was purified via flash columnchromatography (10% EtOAc in hexane) to give(2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a yellow oil(4.81 g, 62% as the major product); ¹HNMR (CDCl₃) δ 7.36 (d, J=8 Hz, 1H,Ar), 6.93 (d, J=2 Hz, 2H, Ar), 6.63 (t, J=2 Hz, 1H, Ar), 6.55 (d, J=2Hz, 1H, Ar), 6.51 (m, 1H), 3.89 (s, 3H, OCH₃), 3.83 (s, 6H, 20CH₃); ¹³CNMR (CDCl₃) δ 195.3, 163.4, 160.6, 159.8, 140.9, 132.2, 121.7, 107.7,105.2, 104.6, 99.1, 55.8, 55.7, 55.6; Anal. Calcd. For C₁₇H₁₈O₅: C,67.54; H, 6.00. Found: C, 67.50; H, 5.88. The product was carried overto the next step.

(2,5-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.25 g, 4.13mmol), cyanomethylphosphonic acid diethyl ester (1.30 ml, 8.26 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 8.26 ml, 8.26 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 20% EtOAc in hexane in about 45 min.) togive an oil (1.27 g), which was further purified via PREP HPLC. The purefractions were concentrated to give3-(2,5-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as anoil (1.13 g, 84%); ¹HNMR (DMSO-d₆) δ 7.12-6.41 (m, 12H, Ar), 6.17 (s,1H, double bond proton), 3.83-3.66 (multiple singlets, 24H, 80CH₃); ¹³CNMR (CDCl₃) δ 162.4, 162.3, 160.9, 160.7, 160.1, 159.4, 159.3, 158.4,141.3, 140.8, 133.3, 131.9, 120.4, 118.9, 118.5, 118.0, 107.2, 105.8,104.9, 104.6, 101.9, 101.7, 99.4, 99.2, 96.7, 96.6, 55.8, 55.7, 55.6,55.6; Anal. Calcd. For C₁₉H₁₉NO₄: C, 70.14; H, 5.89; N, 4.30. Found: C,69.96; H, 5.67; N, 4.68.

4.6.2.7 3,3-Bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acrylonitrile

2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.87 g, 5.28 mmol),6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.25 g, 5.81 mmol), and n-butyllithium (2.33 ml, 5.81 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 40% EtOAc in hexane in about 40 min.) to givebis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol as an oil (1.37 g,86%): ¹HNMR (CDCl₃)

6.87-6.82 (m, 6H, Ar), 5.63 (d, J=3 Hz, 1H, CHOH), 4.22 (s, 8H,2CH₂CH₂), 2.19 (d, J=3 Hz, 1H, OH). The product was carried over to thenext step.

Bis-(2,3-dihydrobenzo[1,4]dioxin-6-yl)methanol (1.32 g, 4.40 mmol) andactivated MnO₂ powder (3.3 g, 38 mmol) were treated in the same manneras described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)methanone was an oil(1.25 g, 95%): ¹HNMR (CDCl₃) δ 7.37-6.90 (m, 6H, Ar), 4.36-4.27 (m, 8H,2CH₂CH₂). The product was carried over to the next step.

Bis-(2,3-dihydrobenzo[1,4]dioxin-6-yl)methanone (1.12 g, 3.75 mmol),cyanomethylphosphonic acid diethyl ester (1.18 ml, 7.51 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 7.51 ml, 7.51 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) togive a foam, which was lyophilized to give3,3-bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acrylonitrile as an lightyellow solid (0.90 g, 75%): mp, 138-140° C.; ¹HNMR (DMSO-d₆) δ 6.98 (d,J=8 Hz, 1H, Ar), 6.91-6.77 (m, 5H, Ar), 6.08 (s, 1H, double bondproton), 4.33-4.24 (m, 4H, 2CH₂CH₂); ¹³C NMR (DMSO-d₆) δ 160.4, 145.6,144.7, 143.2, 143.1, 131.2, 130.0, 122.5, 121.9, 118.6, 117.9, 117.2,117.1, 116.9, 93.3, 64.3, 64.2, 64.0, 64.0. Anal. Calcd. For C₁₉H₁₅NO₄:C, 70.62; H, 4.74; N, 4.33. Found: C, 70.45; H, 4.67; N, 4.20.

4.6.2.8 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile

3,4-dimethoxybenzaldehyde (2.21 g, 13.32 mmol),6-Bromo-2,3-dihydrobenzo[1,4]dioxine (3.15 g, 14.65 mmol), and n-butyllithium (5.86 ml, 14.65 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 40% EtOAc in hexane in about 40 min.) to give(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,4-dimethoxy-phenyl)-methanol asan oil (3.60 g, 89%): ¹HNMR (CDCl₃)

6.93-6.80 (m, 6H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.24 (s, 4H, CH₂CH₂),3.86 (s, 6H, 20CH₃), 2.14 (d, J=3 Hz, 1H, OH). The product was carriedover to the next step.

(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-(3,4-dimethoxyphenyl)methanol (3.60g, 11.91 mmol) and activated MnO₂ powder (10 g, 115 mmol) were treatedin the same manner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theoily product solidified to(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,4-dimethoxy-phenyl)methanone as asolid at rt (3.02 g, 85%): ¹HNMR (CDCl₃) δ 7.44-7.27 (m, 4H, Ar),6.95-6.88 (m, 2H, Ar), 4.36-4.28 (m, 4H, CH₂CH₂), 3.96 (s, 3H, OCH₃),3.94 (s, 3H, OCH₃). The product was carried over to the next step.

(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,4-dimethoxyphenyl)methanone (3.01g, 10.02 mmol), cyanomethylphosphonic acid diethyl ester (3.15 ml, 20.05mmol) in anhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide(1.0 M solution in THF, 20.05 ml, 20.05 mmol) were treated in the samemanner as described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) togive an oil, which was lyophilized to give3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileas an light yellow foam (2.80 g, 86%): ¹HNMR (DMSO-d₆) δ 7.09-6.69 (m,6H, Ar), 6.15 (s, 0.49H, double bond proton of one isomer), 6.09 (s,0.45H, double bond proton of the other isomer), 4.33-4.25 (m, 4H,2CH₂CH₂), 3.83-3.74 (multiple singlets, 20CH₃); ¹³C NMR (DMSO-d₆) δ161.0, 160.9, 150.9, 150.0, 148.6, 148.3, 145.6, 144.7, 143.2, 143.0,131.3, 130.5, 130.1, 129.2, 122.6, 122.4, 122.3, 122.0, 118.7, 118.7,118.0, 117.2, 117.1, 117.0, 112.7, 111.4, 111.2, 111.1, 93.1, 93.0,64.3, 64.2, 64.0, 64.0, 55.6, 55.5. Anal. Calcd. For C₁₉H₁₇NO₄(+0.45H₂O): C, 68.85; H, 5.44; N, 4.23. Found: C, 68.69; H, 5.31; N,4.04.

4.6.2.9 3,3-Bis-benzo[1,3]dioxol-5-yl-acrylonitrile

Benzo[1,3]dioxole-5-carbaldehyde (1.80 g, 11.96 mmol),5-bromobenzo[1,3]dioxole (2.65 g, 13.16 mmol), and n-butyl lithium (5.26ml, 13.16 mmol) were treated in the same manner as described above forthe synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (5% EtOAc inhexane gradient to 40% EtOAc in hexane in about 40 min.) to givebis-benzo[1,3]dioxol-5-yl-methanol as a light brown oil (2.69 g, 83%):¹HNMR (CDCl₃)

6.86-6.74 (m, 6H, Ar), 5.93 (s, 4H, 2CH₂), 5.68 (d, J=3 Hz, 1H, CHOH),2.16 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.

Bis-benzo[1,3]dioxol-5-&l-methanol (2.66 g, 9.77 mmol) and activatedMnO₂ powder (9.5 g, 109 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct bis-benzo[1,3]dioxol-5-yl-methanone was an off-white solid (2.41g, 91%): ¹HNMR (CDCl₃) δ 7.34 (d, J=8 Hz, 2H, Ar), 7.30 (d, J=1 Hz, 2H,Ar), 6.86 (d, J=7 Hz, 2H, Ar), 6.06 (s, 4H, 2CH₂). The product wascarried over to the next step.

Bis-benzo[1,3]dioxol-5-yl-methanone (2.41 g, 8.92 mmol),cyanomethylphosphonic acid diethyl ester (2.81 ml, 17.84 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 17.84 ml, 17.84 mmol) were treated in the same manneras described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (10%EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) togive 3,3-bis-benzo[1,3]dioxol-5-yl-acrylonitrile as an off-white solid(2.11 g, 81%): mp, 126-128° C.; ¹HNMR (DMSO-d₆) δ 7.07-7.03 (2 ds,J=1.84 and J=8 Hz, 2H, Ar), 6.94 (d, J=8 Hz, 1H, Ar), 6.90 (d, J=1 Hz,1H, Ar), 6.86 (dd, J=1.76 and J=7 Hz, 1H, Ar), 6.74 (dd, J=1.82 and J=8Hz, 1H, Ar), 6.13 (s, 1H, double bond proton), 6.12 (s, 2H, CH₂), 6.10(s, 2H, CH₂); ¹³C NMR (DMSO-d₆) δ 160.8, 149.4, 148.4, 147.8, 147.3,132.2, 130.9, 123.8, 123.6, 118.5, 109.4, 108.4, 108.2, 107.7, 101.8,101.6, 93.8. Anal. Calcd. For C₁₇H₁₁NO₄: C, 69.62; H, 3.78; N, 4.78.Found: C, 68.43; H, 3.97; N, 4.37.

4.6.2.103-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile

3-ethoxy-4-methoxybenzaldehyde (0.92 g, 5.12 mmol),6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.21 g, 5.63 mmol), and n-butyllithium (2.25 ml, 5.63 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 40% EtOAc in hexane in about 40 min.) to give(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxy-phenyl)-methanolas a yellow solid (0.91 g, 56%): ¹HNMR (CDCl3)

6.92-6.80 (m, 6H, Ar), 5.68 (d, J=3 Hz, 1H, CHOH), 4.23 (s, 4H, 2CH2),4.07 (q, J=6.90, 14 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 2.13 (d, J=2Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried overto the next step.

(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxyphenyl)methanol(0.91 g, 2.88 mmol) and activated MnO2 powder (5.2 g, 60 mmol) weretreated in the same manner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct(2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxy-phenyl)methanonewas a solid (0.86 g, 95%): ¹HNMR (CDCl₃)

7.42 (d, J=1 Hz, 1H, Ar), 7.39-7.31 (m, 3H, Ar), 6.93 (d, J=8 Hz, 1H,Ar), 6.89 (d, J=8 Hz, 1H, Ar), 4.35-4.29 (m, 4H, 2CH2), 4.16 (q, J=6.91,14 Hz, 2H, CH2CH3), 3.95 (s, 3H, OCH3), 1.49 (t, J=6 Hz, 3H, CH2CH3).The product was carried over to the next step.

(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxyphenyl)methanone(0.83 g, 2.64 mmol), cyanomethylphosphonic acid diethyl ester (0.83 ml,5.28 mmol) in anhydrous THF (20 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 5.28 ml, 5.28 mmol) weretreated in the same manner as described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (10%EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) togive a foam, which was lyophilized to give3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrileas a waxy oil (0.70 g, 78%): ¹HNMR (DMSO-d₆)

7.09-6.73 (m, 6H, Ar), 6.12 (s, 0.5H, double bond proton of one isomer),6.07 (s, 0.5H, double bond proton of the other isomer), 4.33-4.25 (m,4H, CH2CH2 for the two isomers), 4.05-3.97 (m, 2H, CH2CH3), 3.83 (s,1.5H, OCH3 of one isomer), 3.79 (s, 1.5H, OCH3 of the other isomer),1.31 (t, J=6 Hz, 3H, CH2CH3); ¹³C NMR(DMSO-d₆)

161.0, 160.8, 151.0, 150.1, 147.8, 147.4, 145.5, 144.7, 143.2, 143.0,131.3, 130.5, 130.1, 129.2, 122.6, 122.3, 120.0, 118.8, 118.7, 118.0,117.1, 117.1, 117.0, 113.7, 112.1, 111.5, 111.3, 93.0, 92.9, 64.3, 64.2,64.0, 64.0, 63.8, 55.5, 55.5, 14.6, 14.6. Anal. Calcd. For C₂₀H₁₉NO₄(+0.45H₂O): C, 70.08; H, 5.76; N, 4.09. Found: C, 69.91; H, 5.54; N,4.13.

4.6.2.113-(3,5-Dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile

3,5-Dimethoxybenzoyl chloride (5.19 g, 25.87 mmol),1,2,3-trimethoxybenzene (4.35 g, 25.87 mmol) in anhydrous methylenechloride (40 ml), and aluminum chloride (3.79 g, 28.45 mmol) weretreated in the same manner as described above for the synthesis of(2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone. The crudematerial was purified via flash column chromatography (20% EtOAc inhexane) to give(3,5-dimethoxy-phenyl)-(2-hydroxy-3,4-dimethoxy-phenyl)-methanone as ayellow solid (4.15 g, 50%); ¹HNMR (CDCl₃) δ 12.36 (s, 1H, OH), 7.42 (d,J=9 Hz, 1H, Ar), 6.75 (d, J=2 Hz, 2H, Ar), 6.64 (t, J=2 Hz, 1H, Ar),6.47 (d, J=9 Hz, 1H, Ar), 3.94 (s, 6H, 20CH₃), 3.84 (s, 6H, 20CH₃); ¹³CNMR (CDCl₃) δ 200.4, 160.7, 158.9, 158.0, 140.1, 136.9, 130.3, 114.6,107.0, 103.8, 102.9, 60.9, 56.3, 55.7; Anal. Calcd. For C₁₇H₁₈O₆: C,64.14; H, 5.70. Found: C, 64.29; H, 5.42; N, <0.05. The product wascarried over to the next step.

To a mixture of (3,5-dimethoxyphenyl)-(2-hydroxy-3,4-dimethoxyphenyl)methanone (1.59 g, 5.00 mmol) in DMF (25 ml) was added iodomethane (0.62ml, 10.00 mmol), and powdered Na₂CO₃ (1.06 g, 10.00 mmol) at rt. Thesuspension was stirred at 35° C. overnight. DMF was evaporated in vacuoand to the residue was added CH₂Cl₂ (100 ml) and washed with H₂O (3×80ml). The white salt was filtered and the solution was washed with 5 NKOH (4×80 ml), H₂O (1×80 ml), dried over MgSO₄ and concentrated to abrown oil, which was purified via flash column chromatography (20% EtOAcin hexane) to give(3,5-dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)methanone as a clear oil(1.49 g, 90%): ¹HNMR (CDCl₃) δ 7.12 (d, J=8 Hz, 1H, Ar), 6.94 (d, J=2Hz, 2H, Ar), 6.71 (d, J=8 Hz, 1H, Ar), 6.65 (t, J=2 Hz, 1H, Ar), 3.93(s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.81 (s, 6H, 20CH₃), 3.79 (s, 3H,OCH₃); ¹³C NMR (CDCl₃) δ 195.2, 160.7, 156.3, 152.9, 142.2, 140.5,126.6, 125.1, 107.7, 106.8, 105.4, 62.0, 61.1, 56.3, 55.7; Anal. Calcd.For C₁₈H₂₀O₆: C, 65.05; H, 6.07. Found: C, 64.93; H, 6.09. The productwas carried over to the next step.

(3,5-Dimethoxyphenyl)-(2,3,4-trimethoxyphenyl)methanone (11.15 g, 3.46mmol), cyanomethylphosphonic acid diethyl ester (1.09 ml, 6.92 mmol) inanhydrous THF (8 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 6.92 ml, 6.92 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (20%EtOAc in hexane) to give3(3,5-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as apink oil (1.20 g, 98%): ¹HNMR (DMSO-d₆) δ 7.00-6.84 (m, 2H, Ar),6.62-6.59 (m, 1H, Ar), 6.45 (d, J=2 Hz, 2H, Ar), 6.01 (s, 0.51H, doublebond proton), 3.87-3.44 (multiple singlets, 15H, 50CH₃); ¹³C NMR (CDCl₃)δ 160.9, 160.8, 160.7, 160.2, 155.5, 155.4, 152.5, 151.8, 142.7, 142.6,141.4, 140.5, 126.2, 125.8, 125.4, 124.1, 118.0, 117.8, 107.2, 107.0,105.7, 102.0, 101.9, 96.8, 96.6, 61.1, 61.0, 60.9, 56.2, 55.7, 55.6;Anal. Calcd. For C₂₀H₂₁NO₅: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.53;H, 5.84; N, 3.88.

4.6.2.12 Phosphoric acidmono-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl} ester

To a pre-died flask containing a stirred solution of3-(3,5-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)acrylonitrile (0.98g, 3.15 mmol) in anhydrous CH₂Cl₂ (25 ml) was added POCl₃ (0.88 ml, 9.44mmol) at 0° C. The mixture was stirred for 5 min. followed by additionof Et₃N (1.32 ml, 9.44 mmol) and stirred at rt overnight. H₂O (25 ml)was poured into the solution and stirred for 20 min. followed by theextraction with CH₂Cl₂ (3×50 ml). The combined CH₂Cl₂ extracts waswashed with 0.1 N HCl (1×100 ml), dried over MgSO4, filtered andconcentrated to an oil, which was further purified via preparative HPLCto give Phosphoric acidmono-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl} esteras a white solid (0.65 g, 53%): ¹HNMR (DMSO-d₆) δ 11.17 (s, 1H, OH),8.47 (s, 1H, OH), 7.56-6.34 (m, 10H, Ar), 5.65-5.26 (m, 2H, double bondprotons), 3.89-3.67 (multiple singlets, 18H, 60CH₃). ¹³C NMR (DMSO-d₆) δ161.9, 161.2, 160.9, 160.3, 157.5, 156.4, 153.5, 152.8, 145.7, 143.6,142.4, 141.5, 129.2, 127.8, 126.4, 122.1, 119.0, 118.8, 110.2, 109.0,107.7, 105.0, 103.9, 98.8, 97.6, 69.1, 65.0, 64.9, 56.2, 55.7; LC/MS:392 for (M+1)⁺¹ for positive ion mass and 390 for (M−1)⁻¹ for negativeion mass.

4.6.2.133-(2,3,4-Trimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile

3,4,5-Trimethoxybenzoyl chloride (11.07 g, 48.0 mmol),1,2,3-trimethoxybenzene (8.07 g, 48.0 mmol) in anhydrous methylenechloride (60 ml), and aluminum chloride (7.04 g, 52.8 mmol) were treatedin the same manner as described above for the synthesis of(2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)methanone. The crudematerial was purified via flash column chromatography (25% EtOAc inhexane) to give(2-hydroxy-3,4-dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone asa yellow solid (9.44 g, 54%); mp, 135-1370C: ¹HNMR (DMSO-d₆) δ 11.39 (s,1H, OH), 7.35 (d, J=8 Hz, 1H, Ar), 6.97 (s, 2H, Ar), 6.70 (d, J=9 Hz,1H, Ar), 3.89 (s, 3H, OCH₃), 3.81 (s, 6H, 20CH₃), 3.76 (s, 3H, OCH₃),3.74 (s, 3H, OCH₃); ¹³C NMR (DMSO-d₆) δ 197.5, 157.6, 154.6, 152.5,140.8, 136.0, 132.9, 128.7, 115.8, 106.7, 103.6, 60.1, 60.0, 56.0; Anal.Calcd. For C₁₈H₂₀O₇: C, 62.06; H, 5.79. Found: C, 62.05; H, 5.55. Theproduct was carried over to the next step.

(2-hydroxy-3,4-dimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (4.44g, 12.75 mmol), iodomethane (1.59 ml, 25.51 mmol), and Na₂CO₃ (2.7 g,25.51 mmol) were treated in the same manner as described above for thesynthesis of (3,5-Dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)-methanone.The crude material was purified via flash column chromatography (20%EtOAc in hexane) to give(2,3,4-trimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as anoff-white solid (3.88 g, 84%); mp, 122-124° C.: ¹HNMR (CDCl₃) δ 7.11 (d,J=8 Hz, 1H, Ar), 7.08 (s, 2H, Ar), 6.73 (d, J=8 Hz, 1H, Ar), 3.94 (s,6H, 20CH₃), 3.91 (s, 3H, OCH₃), 3.86 (s, 6H, 20CH₃), 3.81 (s, 3H, OCH₃);¹³C NMR (DMSO-d₆) δ 194.4, 156.1, 152.9, 152.7, 142.6, 142.3, 133.5,126.5, 124.9, 107.6, 106.8, 62.1, 61.1, 56.4, 56.3; Anal. Calcd. ForC₁₉H₂₂O₇: C, 62.98; H, 6.12. Found: C, 63.14; H, 6.13. The product wascarried over to the next step.

(2,3,4-trimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (2.87 g, 7.92mmol), cyanomethylphosphonic acid diethyl ester (2.50 ml, 15.84 mmol) inanhydrous THF (15 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 15.84 ml, 15.84 mmol) were treated in the same manneras described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (20%EtOAc in hexane) to give3-(2,3,4-trimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile asan off-white solid (2.32 g, 76%); mp, 125-127° C.: ¹HNMR (DMSO-d₆) δ7.01-6.85 (m, 2H, Ar), 6.63-6.61 (m, 2H, Ar), 5.95 (s, 1H, double bondproton), 3.87-3.32 (multiple singlets, 18H, 60CH₃); ³C NMR (CDCl₃) δ160.6, 160.2, 155.5, 153.3, 153.1, 152.4, 151.8, 142.6, 139.5, 134.7,133.8, 126.2, 125.8, 125.4, 118.4, 118.0, 107.2, 107.1, 106.4, 106.1,104.8, 95.9, 61.2, 61.1, 61.0, 61.0, 56.4, 56.4, 56.2; Anal. Calcd. ForC₂₁H₂₃NO₆ (+0.05H₂O): C, 65.29; H, 6.03; N, 3.63. Found: C, 64.90; H,5.94; N, 3.55.

4.6.2.14 3-(2,3-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

2,3-Dimethoxybenzaldehyde (0.84 g, 5.03 mmol),1-bromo-3,5-dimethoxybenzene (1.20 g, 5.53 mmol), and n-butyl lithium(2.20 ml, 5.53 mmol) were treated in the same manner as described abovefor the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 50% EtOAc in hexane in about 40 min.) to give(2,3-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as a greenishyellow oil (1.36 g, 89%): ¹HNMR (CDCl₃)

7.08-7.01 (m, 1H, Ar), 6.93-6.85 (m, 2H, Ar), 6.57 (d, J=2 Hz, 2H, Ar),6.35 (t, J=2 Hz, 1H, Ar), 5.94 (d, J=6 Hz, 1H, CHOH), 3.86 (s, 3H,OCH₃), 3.76 (s, 6H, 20CH₃), 3.66 (s, 3H, OCH₃), 3.05 (d, J=6 Hz, 1H,OH). The product was carried over to the next step.

(2,3-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanol (1.25 g, 4.11 mmol),and activated MnO₂ powder (2.86 g, 32.9 mmol) were treated in the samemanner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct (2,3-Dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone was anoff-white solid (1.21 g, 98%): ¹HNMR (CDCl₃)

7.14-7.02 (m, 2H, Ar), 6.97 (d, J=2 Hz, 2H, Ar), 6.89 (dd, J=2, 7 Hz,1H, Ar), 6.66 (t, J=2 Hz, 1H, Ar), 3.91 (s, 3H, OCH₃), 3.80 (s, 6H,20CH₃), 3.75 (s, 3H, OCH₃). The product was carried over to the nextstep.

(2,3-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.19 g, 3.94mmol), cyanomethylphosphonic acid diethyl ester (1.24 ml, 7.87 mmol) inanhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 7.9 ml, 7.87 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) togive 3-(2,3-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile asa clear light pink oil (1.16 g, 91%): ¹HNMR (DMSO-d₆) δ 7.21-7.08 (m,2H, Ar), 6.83-6.79 (m, 1H, Ar), 6.62-6.56 (m, 1H, Ar), 6.47-6.46 (m, 2H,Ar), 6.00 (s, 1H, double bond proton), 3.86-3.72 (multiple singlets,12H, 40CH₃): ¹³C NMR (CDCl₃) δ 161.0, 160.9, 160.7, 160.4, 153.2, 153.1,147.3, 146.7, 140.5, 140.1, 133.9, 131.7, 124.3, 124.0, 122.5, 122.2,117.7, 117.5, 114.1, 107.0, 105.7, 102.0, 101.9, 97.8, 97.2, 60.9, 60.7,56.1, 56.0, 55.7, 55.6; Anal. Calcd. For C₁₉H₁₉NO₄: C, 73.20; H, 5.80;N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.

4.6.2.15 3-(2,5-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

3,5-Dimethoxybenzoyl chloride (2.00 g, 9.99 mmol), 1,4-dimethoxybenzene(1.38 g, 9.99 mmol) in anhydrous methylene chloride (10 ml), andaluminum chloride (1.46 g, 10.99 mmol) were treated in the same manneras described above for the synthesis of(2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone. The crudematerial was purified via flash column chromatography (10% EtOAc inhexane gradient to 60% EtOAc in hexane in 40 min.) to give(2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a yellowishgreen oil (1.00 g, 33%); ¹HNMR (CDCl₃) δ 7.02-6.88 (m, 5H, Ar), 6.66 (t,J=2 Hz, 1H, Ar), 3.81 (s, 6H, 20CH₃), 3.78 (s, 3H, OCH₃), 3.69 (s, 3H,OCH₃). The product was carried over to the next step.

(2,5-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.92 g, 3.04mmol), cyanomethylphosphonic acid diethyl ester (0.96 ml, 6.09 mmol) inanhydrous THF (15 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 6.09 ml, 6.09 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (10%EtOAc in hexane gradient to 25% EtOAc in hexane in about 20 min.) togive a brown oil, which was lyophilized to give3-(2,5-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as alight yellow solid (0.88 g, 89%): δ ¹HNMR (CDCl₃) δ 6.94-6.43 (m, 12H,Ar), 5.89 (s, 0.65H, double proton of one isomer), 5.87 (s, 0.84H,double proton of the other isomer), 3.83-3.67 (multiple singlets, 24H,80CH₃). The product was a mixture of two isomers with the ratio of43.6%:56.4%; ¹³C NMR (CDCl₃) δ 161.0, 160.7, 159.9, 159.8, 153.6, 153.5,151.9, 151.2, 140.3, 140.0, 128.9, 126.9, 117.9, 117.5, 117.3, 116.3,116.2, 115.8, 113.2, 107.0, 105.8, 102.0, 102.0, 98.3, 97.4, 56.5, 56.0,56.0, 55.6, 55.6; Anal. Calcd. For C₁₉H₁₉NO₄: C, 70.14; H, 5.89; N,4.30. Found: C, 69.78; H, 5.77; N, 4.20.

4.6.2.16 3-(3,5-Dimethoxy-phenyl)-3-phenyl-acrylonitrile

3,5-Dimethoxybenzaldehyde (2.50 g, 15.04 mmol), bromobenzene (2.60 g,16.55 mmol), and n-butyl lithium (33.10 ml, 13.24 mmol) were treated inthe same manner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 20% EtOAc in hexane in about 30 min.) to give(3,5-Dimethoxy-phenyl)-phenyl-methanol as a light yellow oil (3.14 g,85%). HPLC purity was 83% at 3.01 min. (50/50 ACN/0.1% H₃PO₄). ¹HNMR(CDCl₃) δ 7.39-7.25 (m, 4H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.50-6.34(m,2H, Ar), 5.74 (d, J=3 Hz, 1H, CHOH), 3.75 (s, 6H, 20CH₃), 2.34 (d, J=3Hz, 1H, OH). The product was carried over to the next step.

(3,5-Dimethoxyphenyl)phenylmethanol (0.50 g, 2.05 mmol) and activatedMnO₂ powder (0.89 g, 10.25 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)-methanone. Theproduct (3,5-Dimethoxy-phenyl)-phenyl-methanone was an oil (0.34 g,69%), HPLC purity was 99% at 6.25 min. (50/50 ACN/0.1% H₃PO₄). ¹HNMR(CDCl₃) δ 7.83-7.79 (m, 2H, Ar), 7.61-7.55 (m, 1H, Ar), 7.50-7.44 (m,2H, Ar), 6.92 (d, J=2 Hz, 2H, Ar), 6.67 (t, J=2 Hz, 1H, Ar), 3.82 (s,6H, 20CH₃).The product was carried over to the next step.

(3,5-Dimethoxyphenyl)phenylmethanone (0.34 g, 1.40 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 2.81 ml, 2.81 mmol), andcyanomethylphosphonic acid diethyl ester (0.44 ml, 2.81 mmol) inanhydrous THF (5 ml) were treated in the same manner as described abovefor the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (10%EtOAc in hexane) to give 3-(3,5-dimethoxy-phenyl)-3-phenyl-acrylonitrileas an oil (0.33 g, 89%): ¹HNMR (DMSO-d₆) δ 7.55-7.35 (m, 5H, Ar),6.67-6.62 (2ts, 1H, Ar), 6.48-6.45 (2ds, 2H, Ar), 6.39 (s, 0.57H, doublebond proton of one isomer), 6.34 (s, 0.43H, double bond proton of theother isomer), 3.76 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃); ¹³C NMR (CDCl₃) δ163.2, 163.1, 160.9, 160.9, 141.2, 138.9, 138.7, 137.0, 130.6, 130.2,129.7, 128.8, 128.6, 128.5, 117.9, 117.8, 107.8, 107.0, 102.3, 102.2,95.3, 95.1, 55.7, 55.6; Anal. Calcd. For C₁₇H₁₅NO₂ (+0.03H₂O): C, 76.80;H, 5.71; N, 5.27. Found: C, 76.41; H, 5.40; N, 5.18.

4.6.2.17 3-(3,5-Dimethoxy-phenyl)-3-(2-methoxy-phenyl)-acrylonitrile

2-Methoxybenzaldehyde (0.81 g, 5.95 mmol), 1-bromo-3,5-dimethoxybenzene(1.42 g, 6.54 mmol), and n-butyl lithium (2.62 ml, 6.54 mmol) weretreated in the same manner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 40% EtOAc in hexane in about 40 min.) to give(3,5-dimethoxy-phenyl)-(2-methoxy-phenyl)-methanol as a greenish oil(1.38 g, 85%): ¹HNMR (CDCl₃)

7.30-7.18 (m, 2H, Ar), 6.96-6.88 (m, 2H, Ar), 6.57 (d, J=1 Hz, 2H, Ar),6.36 (t, J=2 Hz, 1H, Ar), 5.99 (d, J=5 Hz, 1H, CHOH), 3.84 (s, 3H,OCH₃), 3.77 (s, 6H, 20CH₃), 3.04 (d, J=5 Hz, 1H, OH). The product wascarried over to the next step.

(3,5-Dimethoxy-phenyl)-(2-methoxy-phenyl)-methanol (1.30 g, 4.74 mmol),and activated MnO₂ powder (3.75 g, 43 mmol) were treated in the samemanner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct (3,5-Dimethoxy-phenyl)-(2-methoxy-phenyl)-methanone was an oil(1.23 g, 95%): ¹HNMR (CDCl₃)

7.49-7.42 (m, 1H, Ar), 7.34-7.31 (m, 1H, Ar), 7.05-6.96 (m, 4H, Ar),6.65 (t, J=2 Hz, 1H, Ar), 3.80 (s, 6H, 20CH₃), 3.75 (s, 3H, OCH₃). Theproduct was carried over to the next step.

(3,5-Dimethoxyphenyl)-(2-methoxyphenyl)methanone (1.22 g, 4.48 mmol),cyanomethylphosphonic acid diethyl ester (1.41 ml, 8.96 mmol) inanhydrous THF (30 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 9.00 ml, 9.00 mmol) were treated in the same manner asdescribed above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (10%EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) togive 3-(3,5-Dimethoxy-phenyl)-3-(2-methoxy-phenyl)-acrylonitrile as anoff-white solid (0.93 g, 70%); mp, 82-84° C.: ¹HNMR (CDCl₃)

7.39-6.90 (m, 8H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.51-6.48 (m, 2H, Ar),6.42 (d, J=2 Hz, 2H, Ar), 5.89 (s, 2H, double bond protons of the twoisomers), 3.78 (s, 6H, 20CH₃), 3.75 (s, 6H, 20CH₃), 3.74 (s, 6H, 20CH₃);¹³C NMR (CDCl₃) δ 160.9, 160.7, 160.2, 159.9, 157.7, 140.6, 140.3,131.6, 131.2, 130.9, 128.0, 126.2, 120.9, 120.7, 118.0, 117.6, 111.8,107.1, 105.8, 101.9, 98.0, 97.3, 55.8, 55.6, 55.6; Anal. Calcd. ForC₁₈H₁₇NO₃: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.08; H, 5.85; N,4.78.

4.6.2.183-(3,5-Dimethoxy-phenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo11,41dioxin-5-yl)-acrylonitrile

6-Bromo-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxine (1.50 g, 5.23mmol), 3,5-dimethoxybenzaldehyde (0.79 g, 4.75 mmol), and n-butyllithium (2.09 ml, 5.23 mmol) were treated in the same manner asdescribed above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (5% EtOAc inhexane gradient to 30% EtOAc in hexane in about 40 min.) to give(3,5-Dimethoxy-phenyl)-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-methanolas an oil (0.47 g, 26%): ¹HNMR (CDCl₃)

7.37 (dd, J=1, 7 Hz, 1H, Ar), 7.17 (t, J=8 Hz, 1H, Ar), 7.06 (dd, J=1, 8Hz, 1H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.38 (t, J=2 Hz, 1H, Ar), 6.12(d, J=3 Hz, 1H, CHOH), 3.77 (s, 6H, 20CH₃),2.36 (d, J=3 Hz, 1H, OH). Theproduct was carried over to the next step.

(3,5-Dimethoxyphenyl)-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-5-yl)methanol(5233-15-C, 0.45 g, 1.20 mmol), and activated MnO₂ powder (2.42 g, 28mmol) were treated in the same manner as described above for thesynthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct(3,5-dimethoxy-phenyl)-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-methanonewas an oil (0.43 g, 96%): ¹HNMR (CDCl₃)

7.32-7.27 (m, 3H, Ar), 6.94 (d, J=2 Hz, 2H, Ar), 6.72 (t, J=2 Hz, 1H,Ar), 3.82 (s, 6H, 20CH₃). The product was carried over to the next step.

(3,5-Dimethoxyphenyl)-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-5-yl)methanone(0.42 g, 1.13 mmol), cyanomethylphosphonic acid diethyl ester (0.36 ml,2.26 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 2.26 ml, 2.26 mmol) weretreated in the same manner as described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 25% EtOAc in hexane in about 30 min.) togive3-(3,5-dimethoxy-phenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-acrylonitrileas an oil (0.42 g, 94%): ¹HNMR (DMSO-d₆)

7.70-7.35 (m, 6H, Ar), 6.86 (s, 0.32H, double bond proton of oneisomer), 6.68-6.66 (m, 2H, Ar), 6.53 (d, J=2 Hz, 1.3H, Ar), 6.48 (d, J=1Hz, 0.7H, Ar), 6.27 (s, 0.62H, double bond proton of the other isomer),3.74 (s, 6H, 20CH₃); ¹³C NMR (DMSO-d₆) δ 160.7, 160.5, 155.0, 153.8,138.0, 137.3, 136.7, 133.7, 128.7, 128.7, 127.8, 127.5, 126.8, 126.7,126.5, 119.5, 119.3, 117.1, 116.9, 106.2, 105.3, 102.5, 101.8, 101.1,100.6, 55.4, 55.4; Anal. Calcd. For C₁₉H₁₃F₄NO₄: C, 57.73; H, 3.31; N,3.54; F, 19.22. Found: C, 57.62; H, 3.34; N, 3.49; F, 19.17.

4.6.2.19 3-(3-Benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile

To a stirred solution of bromomethylbenzene (24.39 g, 143 mmol),3-bromophenol (24.92 g, 144 mmol) in acetone (20 ml) was added potassiumcarbonate (59.72 g, 430 mmol). The suspension was refluxed overnight andthen evaporated. To the residue was added H₂O (100 ml) and extractedwith EtOAc (3×80 ml). The combined EtOAc extracts were back washed withNa₂CO₃ and then dried over MgSO₄, filtered and evaporated to get anoff-white solid, which was purified via flash column chromatography (10%CH₂Cl₂ in hexane) to give 1-benzyloxy-3-bromo-benzene as a white solid(10 g, 67%): ¹HNMR (DMSO-d₆)

7.46-7.00 (m, 9H, Ar), 5.12 (s, 2H, CH₂). The product was carried overto the next step.

1-Benzyloxy-3-bromobenzene (10.56 g, 40.13 mmol),3,5-dimethoxybenzaldehyde (7.34 g, 44.14 mmol), and n-butyl lithium(17.66 ml, 44.14 mmol) were treated in the same manner as describedabove for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. Thecrude material was purified via flash column chromatography (10% EtOAcin hexane gradient to 40% EtOAc in hexane in about 40 min.) to give(3-Benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g,82%): ¹HNMR (CDCl₃)

7.43-7.21 (m, 6H, Ar), 7.04-6.85 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar),6.36 (t, J=2 Hz, 1H, Ar), 5.72 (d, J=3 Hz, 1H, CHOH), 5.04 (s, 2H, CH₂),3.76 (s, 6H, 20CH₃), 2.21 (d, J=3 Hz, 1H, OH). The product was carriedover to the next step.

(3-Benzyloxyphenyl)-(3,5-dimethoxyphenyl)methanol (11.51 g, 32.85 mmol),and activated MnO₂ powder (30 g, 345 mmol) were treated in the samemanner as described above for the synthesis of(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanone. Theproduct (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)methanone was a clearoil (10.67 g, 93%): ¹HNMR (CDCl₃)

7.45-7.33 (m, 8H, Ar), 7.22-7.17 (m, 1H, Ar), 6.92 (d, J=2 Hz, 2H, Ar),6.67 (t, J=2 Hz, 1H, Ar), 5.11 (s, 2H, CH₂), 3.82 (s, 6H, 20CH₃). Theproduct was carried over to the next step.

(3-Benzyloxyphenyl)-(3,5-dimethoxyphenyl)methanone (10.66 g, 30.60mmol), cyanomethylphosphonic acid diethyl ester (9.63 ml, 61.19 mmol) inanhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 Msolution in THF, 61.20 ml, 61.19 mmol) were treated in the same manneras described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography (5%EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) togive 3-(3-benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as awhite solid (9.82 g, 86%): ¹HNMR (DMSO-d₆)

7.47-7.31 (m, 6H, Ar), 7.20-6.88 (m, 3H, Ar), 6.66-6.62 (2ts, 1H, Ar),6.46 (d, J=2 Hz, 2H, Ar), 6.40 (s, 0.5H, double bond proton of oneisomer), 6.38 (s, 0.5H, double bond proton of the other isomer), 5.12(s, 1H, half CH₂), 5.11 (s, 1H, half CH₂), 3.76 (s, 3H, OCH₃), 3.73 (s,3H, OCH₃); ¹³C NMR(DMSO-d₆) δ 161.2, 160.4, 158.4, 158.2, 139.6, 138.9,138.8, 138.3, 136.7, 129.8, 128.4, 127.9, 127.8, 121.5, 120.8, 117.9,117.9, 116.8, 116.0, 115.5, 114.4, 107.1, 106.5, 101.9, 101.1, 96.8,96.5, 69.4, 55.4,53.6; Anal. Calcd. For C₂₄H₂₁NO₃: C, 77.61; H, 5.70; N,3.77. Found: C, 77.39; H, 5.70; N, 3.69.

4.6.2.203-(3,5-Dimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile

(3,5-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (0.55 g, 1.7mmol), cyanomethylphosphonic acid diethyl ester (0.52 ml, 3.3 mmol) inanhydrous THF (20 ml), and potassium bis-(trimethylsilyl)amide (0.66 g,3.3 mmol) were treated in the same manner as described above for thesynthesis of3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile.The crude material was purified by flash column chromatography to give asolid (450 mg, 81%): mp, 135-137° C.; ¹H NMR (DMSO-d₆) δ 6.67-6.63 (m,3H), 6.51 (d, J=1 Hz, 2H), 6.36-6.33 (m, 1H), 3.77-3.71 (m, 15H); ¹³CNMR (DMSO-d₆) δ 161.33, 161.16, 160.38, 160.29, 152.70, 152.65, 139.73,139.63, 138.73, 138.59, 132.82, 132.09, 118.14, 118.05, 107.24, 106.82,106.62, 106.01, 102.36, 96.32, 95.77, 60.11, 56.06, 55.39; Anal. Calcd.For C₂₀H₂₁NO₅: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.44; H, 5.73; N,3.77.

4.6.2.213-(3-Amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers)

Grignard reagent was prepared in an oven-dried three necked flaskoutfitted with a reflux condenser, dropping funnel, and magneticstirrer. Approximately 3 mL of a solution of 3,4-bromoveratrole (3.5 g,15.9 mmol) in THF (10 mL) was added to a mixture of magnesium turnings(0.4 g, 15.9 mmol) in THF (5 mL) with a small piece of iodine. As soonas the solution became colorless (heating sometimes necessary), theremaining 3,4-bromoveratrole solution was added dropwise to the solutionunder mild reflux. The resulting mixture was refluxed for 3 h thencooled to room temperature for 30 min. The(3,4-dimethoxyphenyl)magnesium bromide was then added slowly to astirred solution of 4-methoxy-3-nitro-benzaldehyde (2.4 g, 13.3 mmol) inTHF (10 mL) at 0° C. After complete addition, the solution was allowedto stir at room temperature for 1 h. The mixture was cooled to 0° C. andquenched with saturated NH₄Cl solution (40 mL). The aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith water (2×30 mL), brine (30 mL) and dried (MgSO₄). Solvent wasremoved and residue was purified by flash chromatography (silica gel,CH₂Cl₂: EtOAc 9: 1) to give(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol as an oil(2.6 g, 63%): ¹H NMR (CDCl₃) δ 7.89 (d, J=2 Hz, 1H), 7.54-7.49 (dd, J=2,8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.88-6.81 (m, 3H), 5.78 (d, J=3 Hz,1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (d, J=3 Hz, 1H).

Pyridinium chlorochromate (2.6 g, 12.2 mmol) and Celite (1 g) was addedto a stirred solution of(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (2.6 g, 8.1mmol) in CH₂Cl₂ (100 mL). The mixture was stirred for 4 h at roomtemperature then filtered through Celite. The filtrate was washed withwater (2×40 mL), brine (40 mL) and dried (MgSO₄). Solvent was removedand the residue was purified by flash chromatography (silica gel,CH₂Cl₂: EtOAc 95: 5) to give(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (2.0 g,76%): ¹H NMR (CDCl₃) δ 8.29 (d, J=2 Hz, 1H), 8.07-8.03 (dd, J=2, 8 Hz,1H), 7.34 (d, J=1 Hz, 1H), 7.35-7.26 (dd, J=2, 8 Hz, 1H), 7.21 (d, J=8Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.06 (s. 3H), 3.98 (s, 3H), 3.95 (s, 3H);¹³C NMR (CDCl₃) δ 192.10, 155.48, 153.34, 149.29, 139.01, 135.57,130.35, 129.49, 127.60, 124.94, 113.14, 111.98, 109.96, 56.86, 56.13,56.07.

Lithium bis (trimethylsilyl)amide (7.2 mL, 7.2 mmol) was added slowly toa stirred solution of diethyl cyanomethylphosphate (1.2 g, 6.6 mmol) inTHF (15 mL) at 4-6° C. The resulting solution was stirred at roomtemperature for 40 min. then added to a stirred mixture of(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (1.9 g, 6.0mmol) in THF (25 mL). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water (40mL) and extracted with CH₂Cl₂ (3×30 mL). The combined organic extractswere washed with water (2×40 mL), brine (40 mL) and dried (MgSO₄).Solvent was removed and the residue was purified by flash chromatography(silica gel, Hexane: CH₂Cl₂ 5: 95) to give a mixture of isomers of3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (1.8g, 88%) as a yellow solid: ¹H NMR (CDCl₃) δ 7.86-7.50 (m, 2H), 7.27-6.79(m, 4H), 5.69 (5.61) (s, 1H), 4.04 (4.01) (s, 3H), 3.95 (3.92) (s, 3H),3.88 (3.85) (s, 3H); ¹³C NMR (CDCl₃) δ 159.93, 153.94 (154.14), 151.61(151.04), 149.20 (148.92), 139.92, 135.31 (133.97), 130.50 (131.57),129.32 (128.33), 127.10 (125.72), 122.25 (123.10), 117.78 113.54(112.43), 111.03 (110.87), 93.72 (93.93), 56.78 (56.73), 56.09,56.04(55.97).

A mixture of3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (1.8g, 5.3 mmol) and 10% Pd/C (0.2 g) in EtOAc (100 mL) was hydrogenated at50 psi of hydrogen overnight. The reaction mixture was filtered throughCelite and the filtrate was concentrated. The crude product was purifiedby flash chromatography (silica gel, CH₂Cl₂: EtOAc 9: 1) to give amixture of isomers of3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (0.9g, 54%) as a yellow solid: mp 99-101° C.; ¹H NMR (CDCl₃) δ 7.06-8.65 (m,6H), 5.52 (5.51) (s, 1H), 3.93-3.86 (m, 9H), 3.82 (s, 2H); ¹³CNMR(CDCl₃) δ 162.89, 150.90 (150.10), 149.12 (148.68), 148.72 (148.51),135.94 (136.13), 132.17 (131.99), 129.84, 122.15 (123.10), 120.66(119.66), 118.81 (118,73), 115.93 (114.57), 111.45 (112.81), 110.66(109.79), 91.54 (91.49), 77.20, 56.03, 55.96, 55.90, (55.56, 55.49);Anal Calcd for C₁₈H₁₈N₂O₃+0.1H₂O: C, 69.26; H, 5.88; N, 8.97. Found: C,68.88; H, 5.81; N, 8.78.

Acetyl chloride (0.1 mL, 1.6 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (0.4g, 1.2 mmol) in THF (20 mL). The solution was refluxed for 30 min thencooled to room temperature. The reaction mixture was quenched withmethanol (0.5 mL) and concentrated. The residue was stirred with hexane(20 mL) to afford a mixture of isomers ofN-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.3 g, 81%) as a yellow solid: mp 139-141° C.; ¹H NMR (CDCl₃) δ 8.48(8.35) (d, J=1 Hz, 1H), 7.75 (s, 1H), 7.21-6.80 (m, 5H), 5.60 (5.59) (s,1H), 3.94-3.83 (m, 9H), 2.20 (2.17) (s, 3H); ¹³C NMR (CDCl₃) δ 168.26(168.08), 162.54 (162.25), 151.10 (150.45), 149.35 (148.94), 148.82(148.56), 131.99 (131.48), 129.88 (129.52), 127.79 (127.50), 125.40(124.81), 123.07 (122.21), 121.24 (119.56), 118.60 (118.50), 112.78(111.25), 110.74 (110.69), 109.56 (109.51), 92.53 (92.31), 56.01, 55.97,55.86 (55.80), 15.55 (24.81); Anal Calcd for C₂₀H₂₀N₂O₄+0.06H₂O: C,67.96; H, 5.74; N, 7.93. Found: C, 67.66; H, 5.88; N, 7.82.

4.6.2.22N-{5-[2-Cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(E and Z isomers)

Acetyl chloride (0.1 mL, 1.6 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (0.4g, 1.2 mmol) in THF (20 mL). The solution was refluxed for 30 min thencooled to room temperature. The reaction mixture was quenched withmethanol (0.5 mL) and concentrated. The residue was stirred with hexane(20 mL) to afford a mixture of isomers ofN-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.3 g, 81%) as a yellow solid: mp 139-141° C.; ¹H NMR (CDCl₃) δ 8.48(8.35) (d, J=1 Hz, 1H), 7.75 (s, 1H), 7.21-6.80 (m, 5H), 5.60 (5.59) (s,1H), 3.94-3.83 (m, 9H), 2.20 (2.17) (s, 3H); ¹³C NMR (CDCl₃) δ 168.26(168.08), 162.54 (162.25), 151.10 (150.45), 149.35 (148.94), 148.82(148.56), 131.99 (131.48), 129.88 (129.52), 127.79 (127.50), 125.40(124.81), 123.07 (122.21), 121.24 (119.56), 118.60 (118.50), 112.78(111.25), 110.74 (110.69), 109.56 (109.51), 92.53 (92.31),56.01,55.97,55.86 (55.80),15.55 (24.81); Anal Calcd forC₂₀H₂₀N₂O₄+0.06H₂O: C, 67.96; H, 5.74; N, 7.93. Found: C, 67.66; H,5.88; N, 7.82.

4.6.2.233-(3-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(E and Z isomers)

(4-Methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol wasprepared analogously to(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-methanol using3,4,5-tromethoxybromobenzene (4.4 g, 17.8 mmol), magnesium turning (0.4g, 17.8 mmol) and 4-methoxy-3-nitro-benzaldehyde (2.7 g, 14.4 mmol). Thecrude product was purified by flash chromatography (silica gel, CH₂Cl₂:EtOAc 9: 1) to afford(4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl0-methanol (2.4 g,46%): ¹H NMR (CDCl₃) δ 7.88 (d, J=0.2 Hz, 1H), 7.53-7.49 (dd, J=2, 8 Hz,1H), 7.05 (d J=8 Hz, 1H), 6.54 (s, 2H), 5.72 (d, J=3 Hz, 1H), 3.94 (s,3H), 3.91 (s, 3H), 3.81 (s, 6H), 3.02 (d, J=3 Hz, 1H).

(4-Methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone wasprepared analogously to(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using(4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.4 g,6.9 mmol) and pyridinium chlorochromate (2.2 g, 10.3 mmol). The crudeproduct was purified by flash chromatography (silica gel, CH₂Cl₂: EtOAc95: 5) to afford(4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.3 g,55%) as a white solid: ¹H NMR (CDCl₃) δ 8.34 (d, J=2 Hz, 1H), 8.10-8.06(dd, J=2, 8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.01 (s, 2H), 4.07 (s, 3H),3.95 (s, 3H), 3.87 (s, 3H).

3-(4-Methoxy-3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrilewas prepared analogously to3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing 3-(4-methoxy-3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-methanone(1.3 g, 3.7 mmol), lithium bis (trimethylsilyl)amide (4.5 mL, 4.5 mmol)and diethyl cyanomethylphosphate (0.7 g, 4.1 mmol). The crude productwas purified by flash chromatography (silica gel, CH₂Cl₂: EtOAc 95: 5)to afford a 1:1 mixture of isomers of3-(4-methoxy-3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.9 g, 65%): ¹H NMR (CDCl₃) δ 7.88-7.85 (m, 1H), 7.83-7.48 (dd, J=2, 8Hz, 1H), 7.22-7.12 (d, J=8 Hz, 1H), 6.46 (6.63) (s, 2H), 5.70 (5.66) (s,1H), 4.04 (4.01) (s, 3H), 3.90 (3.93) (s, 3H), 3.81 (3.84) (s,6H).

3-(3-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrilewas prepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing3-(4-methoxy-3-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.9 g, 2.4 mmol) and 10% Pd/C (0.1 g). The crude product was purifiedby flash chromatography (silica gel, CH₂Cl₂: EtOAc 85: 15) to afford amixture of isomers of3-(3-amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.3 g, 41%) as a yellow solid: mp 97-99° C.; ¹H NMR (CDCl₃) δ 6.87-6.51(m, 5H), 5.75 (5.51) (s, 1H), 3.91-3.80 (m, 14H); ¹³C NMR (CDCl₃) δ163.04 (163.13), 152.97 (152.89), 149.22 (148.80), 1139.26 (139.85),136.19(135.96), 132.58(135.12), 131.52(129.53), 119.53(120.75), 114.38(115.88), 109.83 (109.77), 107.20 (106.21), 92.10 (92.56), 60.91, 56.25,55.56, 55.49; Anal Calcd for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N, 8.23.Found: C, 67.08; H, 6.08; N, 7.94.

4.6.2.243-(2-Amino-5-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(E and Z isomers)

(5-Methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol wasprepared analogously to(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using3,4,5-trimethoxy-bromobenzene (4.6 g, 18.5 mmol), magnesium turning (0.5g, 18.5 mmol) and 5-methoxy-2-nitro-benzaldehyde (2.8 g, 15.5 mmol). Thecrude product was purified by flash chromatography (silica gel, CH₂Cl₂:EtOAc 9: 1) to afford(5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.9 g,53%); ¹H NMR (CDCl₃) δ 8.08 (d, J=9 Hz, 1H), 7.20 (d, J=2 Hz, 1H),6.91-6.87 (dd, J=3, 9 Hz, 1H), 6.57 (s, 2H), 6.45 (d, J=4 Hz, 1H), 3.88(s, 3H), 3.82 (s, 3H), 3.80 (s, 6H), 3.04 (d, J=4 Hz, 1H).

(5-Methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone wasprepared analogously to(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using(5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.9 g,8.2 mmol) and pyridinium chlorochromate (2.6 g, 12.2 mmol). The crudeproduct was purified by flash chromatography (silica gel, CH₂Cl₂: EtOAc95: 5) to afford(5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (2.2 g,76%) as a white solid: ¹H NMR (CDCl₃) δ 8.22 (d, J=9 Hz, 1H), 7.11-7.06(dd, J=3, 9 Hz, 1H), 7.00 (s, 2H), 6.89 (d, J=2 Hz, 1H), 3.93 (s, 3H),3.92 (s, 3H), 3.82 (s, 6H); ¹³C NMR (CDCl₃) δ 191.95, 164.01, 153.25,143.37, 139.57, 138.57, 130.85, 126.93, 115.30, 113.49, 106.78, 60.93,56.32, 56.25.

3-(5-Methoxy-2-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrilewas prepared analogously to3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone(2.2 g, 6.2 mmol), lithium bis (trimethylsilyl)amide (9.3 mL, 9.3 mmol)and diethyl cyanomethylphosphate (1.6 g, 9.3 mmol). The product waspurified by flash chromatography (silica gel, Hexane: EtOAc 6: 4) toafford mixture of isomers of3-(5-methoxy-2-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(2.2 g, 93%): ¹H NMR (CDCl₃) δ 8.12 (8.27) (d, J=9 Hz, 1H), 7.07-7.03(dd, J=3, 9 Hz, 1H), 6.91 (6.97) (d, J=2 Hz, 1H), 6.68 (6.43) (s, 2H),5.49 (5.89) (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.79 (6H).

3-(2-Amino-5-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrilewas prepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing3-(5-methoxy-2-nitro-phenyl)-37-(3,4,5-trimethoxy-phenyl)-acrylonitrile(1.5 g, 4.0 mmol) and 10% Pd/C (0.2 g). The crude product was purifiedby flash chromatography (silica gel, CH₂Cl₂: EtOAc 85: 15) to afford asingle isomer of3-(2-amino-5-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.3 g, 25%) as a yellow solid: mp 132-134° C.; ¹H NMR (CDCl₃) δ6.87-6.82 (dd, J=3, 8 Hz, 1H), 6.81 (s, 2H), 6.68 (d, J=2 Hz, 1H), 6.64(d, J=8.8 Ha, 1H), 5.58 (s, 1H), 3.90 (s, 3H), 3.83 (s, 6H), 3.77 (s,3H), 3.28 (b, 2H); ¹³C NMR (CDCl₃) δ 161.09, 153.38, 152.40, 140.15,138.26, 131.07, 125.44, 117.94, 117.84, 117.24, 115.55, 106.15, 96.46,60.95, 55.79, 55.32; Anal Calcd for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N,8.23. Found: C, 67.02; H, 6.02; N, 8.07.

4.6.2.253-(4-Methoxy-3-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers)

(4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was preparedanalogously to3-(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using3,5-dimethoxy-bromobenzene (5.0 g, 23.0 mmol), magnesium turning (0.6 g,23.0 mmol) and 4-methoxy-3-nitro-benzaldehyde (3.5 g, 19.2 mmol). Thecrude product was purified by flash chromatography (silica gel, Hexane:EtOAc 1:1) to afford(4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 60%)as an oil: ¹H NMR (CDCl₃) δ 7.88 (s, 1H), 7.54-7.50 (dd, J=2, 8 Hz, 1H),7.04 (d, J=8 Hz, 1H), 6.38 (d, J=1 Hz, 1H), 5.72 (d, J=3 Hz, 1H), 3.93(s, 3H), 3.76 (s, 6H), 2.45 (d, 2 Hz, 1H).

(4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone was preparedanalogously to(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using(4-methosy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 11.5mmol) and pyridinium chlorochromate (3.7 g, 17.0 mmol). The crudeproduct was purified by flash chromatography (silica gel, CH₂Cl₂: EtOAc9: 1) to afford(4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.0 g, 82%)as a white solid: ¹H NMR (CDCl₃) δ 8.33 (d, J=2 Hz, 1H), 8.09 (d, J=9.1Ha, 1H), 7.20-7.15 (dd, J=3, 8 Hz, 1H), 6.84 (d, J=2 Hz, 2H), 6.69 (m,1H), 4.06 (s, 3H), 3.83 (s, 6H).

3-(4-Methoxy-3-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers) were prepared analogously to3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.0g, 9.5 mmol), lithium bis (trimethylsilyl)amide (10.4 mL, 10.4 mmol) anddiethyl cyanomethylphosphate (1.9 g, 10.4 mmol). The crude product waspurified by flash chromatography (silica gel, Hexane: CH₂Cl₂ 1: 9) toafford mixture of isomers of3-(4-methoxy-3-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (2.9g, 91%) as a yellow solid: mp 122-124° C.; ¹H NMR (CDCl₃) δ 7.85-7.78(m, 1H), 7.20 (d, J=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 6.57-6.54 (m, 1H),6.51 (d, J=2 Hz, 1H), 6.37 (d, J=2 Hz, 1H), 5.75 (s, 1H), 4.03 (4.00)(s. 3H), 3.80 (3.77) (s, 6H); ¹³C NMR (CDCl₃) δ 161.04, 160.98, 160.26,154.04, 135.18, 133.75, 130.90, 129.05, 127.10, 125.40, 113.61, 113.55,56.80, 56.75, 55.53; Anal Calcd for C₁₈H₁₆N₂O₅: C, 63.53; H, 4.74; N,8.23. Found: C, 63.35; H, 4.50; N, 8.19.

4.6.2.263-(3-Amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers)

3-(3-Amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers) was prepared analogously to3-(4-amino-3-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrileusing3-(4-methoxy-3-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (1.5g, 4.4 mmol) and tin chloride dihydrate (5.4 g, 23.0 mmol). The crudeproduct was purified by flash chromatography (silica gel, Hexane: EtOAc75: 25) to afford mixture of isomers of3-(3-amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (0.8g, 54%) as a yellow solid: mp 93-95° C.; ¹H NMR (CDCl₃) δ 6.82-6.42 (m,6H), 5.54 (s, 1H), 3.89 (3.87) (s, 3H), 3.87-3.70 (b, 2H), 3.79 (3.73)(s, 6H); ¹³C NMR (CDCl₃) δ 163.14, 162.93, 160.60, 160.55, 149.22,148.78, 141.73, 139.25, 136.17, 135.95, 131.24, 129.54, 120.67, 119.36,115.82, 114.23, 109.86, 109.80, 107.64, 107.00, 101.97, 101.92, 93.36,92.65, 55.57, 55.46; Anal Calcd for C₁₈H₁₈N₂O₃: C, 69.66; H, 5.85; N,9.03. Found: C, 69.60; H, 5.58; N, 8.88.

4.6.2.27N-{5-[2-Cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy}-acetamide (Eand Z isomers)

Acetyl chloride (0.2 mL, 2.6 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)acrylonitrile (0.4g, 1.3 mmol) in THF (20 mL). The solution was refluxed for 30 min thencooled to room temperature. The reaction mixture was quenched withmethanol (0.5 mL) and concentrated. The crude product was purified byflash chromatography (silica gel, Hexane: EtOAc 1:1) to afford a mixtureof isomers ofN-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy}-acetamide (0.3g, 62%) as a white solid: mp 163-165° C.; ¹H NMR (CDCl₃) δ 9.28 (s, 1H),7.93 (s, 1H), 7.17 (m, 2H), 6.62 (s, 1H), 6.46 (d, J=1 Hz, 2H), 6.22(6.14) (s, 1H), 3.91 (s, 3H), 3.76 (s, 6H), 2.06 (s, 3H); ¹³C NMR(CDCl₃) δ 168.67, 161.28, 160.34, 150.52, 140.25, 128.54, 127.28,125.48, 122.49, 118.27, 110.86, 106.68, 101.99, 95.35, 55.84, 55.37,23.81; Anal Calcd for C₂₀H₂₀N₂O₄: C, 68.17; H, 5.72; N, 7.95. Found: C,68.03; H, 5.54; N, 7.85.

4.6.2.284-Amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}butyramideHydrochloride (E and Z isomers)

N-BOC-γ-Aminobutyric acid (0.5 g, 2.4 mmol) was added to a stirredsolution of3-(3-amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.7 g, 2.0 mmol), dicyclohexylcarbodiimide (0.5 g, 2.4 mmol) and1-hydroxybenzotriazole (0.4 g, 3.0 mmol) in DMF (10 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (15 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50mL) and was washed with water (3×30 mL), brine (30 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (silica gel, CH₂CH₂: EtOAc 9: 1) to afford mixture ofisomers ofN-BOC-4-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-butyramide(0.6 g, 57%): ¹H NMR (CDCl₃) δ 8.00 (b, 1H), 7.23-6.84 (m, 3H), 6.51(6.65) (s, 2H), 5.60 (5.66) (s, 1H), 4.71 (b, 1H), 3.95 (3.92 (s, 3H),3.91 (3.92) (s, 3H), 3.80 (3.83) (s, 6H), 3.24-3.19 (m, 2H), 2.46-2.39(m, 2H), 1.94-1.82 (m, 2H), 1.42 (s, 9H).

A solution of 4N HCl/dioxane (2.0 mL) was added to a stirred solution ofN-BOC-4-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-butyramide(0.6 g, 1.1 mmol) in CH₂Cl₂ (10 mL). The solution was stirred at roomtemperature overnight. Ether (10 mL) was added and the mixture wasstirred for 2 h. The slurry was filtered and washed with ether to givemixture of isomers of4-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}butyramidehydrochloride (0.5 g, 90%) as a white solid: mp 168-170° C.; ¹H NMR(DMSO-d₆) δ 9.35 (s, 1H), 8.06 (b, 3H), 7.93 (s, 1H), 7.25-7.09 (m, 2H),6.67 (6.65) (s, 2H), 6.23 (6.10) (s, 1H), 3.92 (3.88) (s, 3H), 3.76-3.71(m, 9H), 2.79 (t, J=7 Hz, 2H), 2.50-2.45 (m, 2H), 1.86-1.77 (m, 2H); ¹³CNMR (DMSO-d₆) δ 170.66 (173.68), 161.15 (161.31), 152.65 (152.61),151.91 (150.90), 139.46 (138.52), 133.52 (132.25), 129.63 (128.44),127.01 (126.89), 125.25 (126.04), 123.18 (122.66), 118.57 (118.53),111.22 (110.93), 106.96 (106.25), 94.36 (93.45), 66.32, 60.12, 56.00(55.87), 38.29 (38.13), 32.74 (30.49), 23.05 (22.46); Anal Calcd forC₂₃H₂₈N₃O₅Cl+1.0H₂O: C, 57.56; H, 6.30; N, 8.75; Cl, 7.39. Found: C,57.72; H, 6.18; N, 8.80; Cl, 8.28.

4.6.2.292-Amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamidehydrochloride (E and Z isomers)

N-BOC-glycine (0.5 g, 2.8 mmol) was added to a stirred solution of3-(3-amino-4-methyoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)acrylonitrile(0.8 g, 2.4 mmol), dicyclohexylcarbodiimide (0.6 g, 2.8 mmol) and1-hydroxybenzotriazole (0.5 g, 3.5 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (15 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50mL) and was washed with water (3×30 mL), brine (30 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (silica gel, CH₂Cl₂: EtOAc 9: 1) to afford mixture ofisomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.9 g, 75%): ¹H NMR (CDCl₃) δ 8.42-8.39 (m, 2H), 6.97-6.85 (m, 1H),6.50 (6.65) (s, 2H), 5.61 (5.65) (s, 1H), 3.94-3.80 (m, 14H), 1.48 (s,9H).

A solution of 4N HCl/dioxane (2.0 mL) was added to a stirred solution ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.9 g, 1.8 mmol) in CH₂Cl₂ (10 mL). The solution was stirred overnight.Ether (10 mL) was added and the mixture was stirred for 2 h. The slurrywas filtered and washed with ether to give mixture of isomers of2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamidehydrochloride (0.7 g, 89%) as a white solid: mp 192-194° C.; ¹H NMR(DMSO-d₆) δ 9.94 (9.90) (s, 1H), 8.27 (b, 3H), 7.79 (7.88) (s, 1H),7.31-7.20 (m, 2H), 6.65 (6.68) (s, 2H), 6.23 (6.13) (s, 1H), 3.94-3.71(m, 14H); ¹³C NMR (DMSO-d₆) δ 165.30 161.02 (161.22), 152.65, 150.83(151.62), 139.41 (138.43), 133.62 (132.29), 128.58 (129.80), 126.15(126.52), 125.22, 123.01 (122.55), 118.48, 111.20 (111.58), 106.27(106.88), 94.43 (93.66), 66.33, 60.12, 56.00 (55.96), 40.92; Anal Calcdfor C₂₁H₂₄N₃O₅Cl+0.75H₂O: C, 56.38; H, 5.74; N, 9.39; Cl, 7.92. Found:C, 56.22; H, 5.76; N, 9.13; Cl, 7.75.

4.6.2.302-Amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamideHydrochloride (E and Z isomers)

N-BOC-L-Alanine (0.5 g, 2.7 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.8 g, 2.2 mmol), dicyclohexylcarbodiimide (0.6 g, 2.7 mmol) and1-hydroxybenzotriazole (0.5 g, 3.4 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (15 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50mL) and was washed with water (3×30 mL), brine (30 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (silica gel, CH₂Cl₂: EtOAc 9: 1) to afford mixture ofisomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(0.8 g, 72%): ¹H NMR (CDCl₃) δ 8.55 (b, 1H), 8.40 (s, 1 h), 7.25-6.85(m, 2H), 6.50 (6.55) (s, 2H), 5.61 (5.66 (s, 1H), 5.04 (d, J=7 Hz, 1H),4.33 (b, 1H), 3.94-3.80 (m, 12H), 1.47-1.41 (m, 12H).

A solution of 4N HCl/dioxane (2.0 mL) was added to a stirred solution ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(0.8 g, 1.6 mmol) in CH₂Cl₂ (20 mL). The mixture was stirred at roomtemperature overnight. Ether (35 mL) was added and the mixture wasstirred for 2 h. The slurry was filtered and was washed with ether togive mixture of isomers of2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamidehydrochloride (0.6 g, 76%) as a white solid: mp 180-182° C.; ¹H NMR(DMSO-d₆) δ 9.98 (9,93) (s, 1H), 8.36 (b, 3H), 7.89-7.84 (m, 1H),7.40-7.16 (m, 2H), 6.65 (6.68) (s, 2H), 6.25 (6.14) (s, 1H), 4.21-4.16(m, 1H), 3.94 (3.91) (s, 3H), 3.76-3.70 (m, 9H), 1.44-1.33 (m, 3H); ¹³CNMR (DMSO-d₆) δ 168.84, 160.92 (161.14), 152.65, 151.31 (152.05), 139.42(138.45), 133.55 (132.24), 128.52 (129.77), 126.88 (126.09), 25.96(125.61), 123.61 (122.97), 118.51 (118.47), 111.26 (111.60), 106.28(106.91), 94.45 (93.67), 60.32, 60.15 (60.12), 56.11 (56.00), 48.59,17.40; Anal Calcd for C₂₂H₂₆N₃O₅Cl+1.2H₂O: C, 56.28; H, 6.10; N, 8.95;Cl, 7.55. Found: C, 55.98; H, 6.07; N, 9.07; Cl, 7.81.

4.6.2.314-Amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-butyramideHydrochloride (E and Z isomers)

N-BOC-γ-aminobutyric acid (0.6 g, 3.0 mmol) was added to stirredsolution of3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(0.8 g, 2.5 mmol), dicyclohexylcarbodiimide (0.6 g, 3.0 mmol) and1-hydroxybenzotriazole (0.5 g, 3.7 mmol) in DMF (15 mL). The resultingmixture was stirred at room temperature for 2 days. Ethyl acetate (15mL) was added and the mixture was filtered. The filtrate was dilutedwith EtOAc (50 mL) and was washed with water (3×30 mL), brine (30 mL)and dried (MgSO₄). Solvent was removed and the residue was purified byflash chromatography (silica gel, CH₂Cl₂: EtOAc 9: 1) to affordN-BOC-4-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-butyramide(1.1 g, 89%): ¹H NMR (CDCl₃) δ 7.95 (b, 1H), 7.32-6.81 (m, 6H), 5.57(5.59) (s, 1H), 4.06-4.01 (q, 2H), 3.94 (3.91) (s,3H), 3.89 (s, 3H),3.21-3.18 (m, 2H), 2.45-2.40 (m, 2H), 1.93-1.85 (m, 2H), 1.47-1.42 (t,3H), 1.42 (s, 9H).

A solution of 4N HCl/dioxane (2 mL) was added to a stirred solution ofN-BOC-4-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}butyramide(1.1 g, 1.2 mmol) in CH₂Cl₂ (15 mL). The resulting mixture was stirredovernight. Ether (30 mL) was added and the mixture was stirred for 2 h.The slurry was filtered and washed with ether to afford mixture isomersof 4-amino-N-{5-[2-cyano-1-1(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}butyramideHydrochloride (0.85 g, 88%) was a white solid: mp 162-164° C.; ¹H NMR(DMSO-d₆) δ 9.30 (s, 1H), 8.03 (s, 3H), 7.95 (7.92 (s, 1H), 7.18-6.74(m, 5H), 6.15 (5.97) (s, 1H), 4.02 (q, J=6 Hz, 2H), 3.943.92) (s, 3H),3.79 (3.83) (s, 3), 2.81-2.75 (m, 2H), 2.53-2.45 (m, 2H), 1.88-1.79 (m,2H), 1.31 (t, J=6 Hz, 3H); ¹³C NMR (DMSO-d₆) δ 170.62, 161.26 (161.47),151.05 (151.66), 150.21 (150.47), 147.31 (147.77), 130.30 (130.45),128.98 (129.17), 127.04 (126.71), 125.70 (125.21), 122.43 (122.21),118.79 (118.72), 113.83 (112.19), 111.46 (111.13), 92.84 (92.56), 63.79(63.74), 55.95 (55.87), 55.55 (55.48), 38.03, 32.76 (32.69), 23.01,14.59 (14.56); Anal Calcd for C₂₃H₂₈N₃O₄Cl+0.58H₂O: C, 60.53; H, 6.44;N, 9.21; Cl, 7.77. Found: C, 60.27; H, 6.20; N, 9.90; Cl, 7.65.

4.6.2.322-Amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamideHydrochloride (E and Z isomers)

N-BOC-glycine (0.5 g, 3.0 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(0.8 g, 2.5 mmol), dicyclohexylcarbodiimide (0.6 g, 3.0 mmol) and1-hydroxybenzotriaole (0.5 g, 3.7 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (15 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50mL) and was washed with water (3×30 mL), brine (30 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (silica gel, CH₂Cl₂: EtOAc 9: 1) to afford a mixture ofisomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.9 g, 75%): ¹H NMR (CDCl₃) δ 8.47-8.37 (m, 2H), 7.01-6.80 (m, 5H),5.58 (s, 1H), 5.20 (b, 1H), 4.12-4.07 (q, 2H), 3.98-3.89 (m, 6H),1.94-1.89 (m, 1H), 1.73-1.67 (m, 1H), 1.48-1.43 (m, 12H).

A solution of 4N HCl/dioxane (3 mL) was added to a stirred solution ofN-BOC-2-amino-N-{5-[2-cyano-1-1(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (1.1 g,2.4 mmol) in CH₂Cl₂ (35 mL). The resulting solution was stirred at roomtemperature overnight. Ether (10 mL) was added and the mixture wasstirred for 2 h. The slurry was filtered and was washed with ether toafford mixture isomers ofE-2-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamidehydrochloride (0.44 g, 44%) as a white solid: mp, 208-210° C.; ¹H NMR(DMSO-d₆) δ 9.88 (s, 1H), 8.20 (b, 3H), 7.89 (d, J=1 Hz, 1H), 7.36-6.91(m, 5H), 6.01 (s, 1H), 3.99 (q, J=7 Hz, 2H), 3.90 (s, 3H), 3.83 (s, 3H),3.78 (s, 2H), 1.31 (t, J=6 Hz, 3H); ¹³C NMR (DMSO-d₆) δ 165.39, 161.37,151.39, 150.15, 147.37, 130.45, 129.21, 126.22, 125.24, 122.36, 118.73,113.75, 111.48, 92.81, 63.75, 56.06, 55.50, 40.97, 14.59; Anal Calcd forC₂₁H₂₄N₃O₄Cl+1.4H₂O: C, 56.92; H, 6.10; N, 9.48; Cl, 8.00. Found: C,56.58; H, 5.85; N, 9.72; Cl, 8.47.

4.6.2.332-Amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-hydroxy-propionamideHydrochloride (E and Z isomers)

N-Fmco-O-t-Bu-L-Ser (1.1 g, 2.8 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.8 g, 2.4 mmol), dicyclohexylcarbodiimide (0.6 g, 2.8 mmol) and1-hydroxybenzotriazole (0.5 g, 3.5 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (15 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50mL) and was washed with water (3×40 mL), brine (40 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatograph (silica gel, Hexane: EtOAc 1:1) to affordN-Fomc-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide(1.5 g, 89%).

A solution ofN-Fmco-2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide(1.5 g, 2.1 mmol) and pyridine (2 mL) in CH₂Cl₂ (20 mL) was stirred for2 h. The mixture was diluted with CH₂Cl₂ (40 mL) and was washed withwater (2×30 mL), brine (30 mL) and dried (MgSO₄). Solvent was removedand the residue was purified by flash chromatography (silica gel,CH₂Cl₂: EtOAc 7: 3) to afford2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide(0.5 g, 53%): ¹H NMR (CDCl₃) δ 8.48 (8.65) (s, 1H), 7.24-6.58 (m, 3H),6.51 (6.66) (s, 2H), 5.60 (5.67) (s, 1H), 3.96-3.79 (m, 12H), 3.69-3.57(m, 3H), 1.21 (1.19) (s, 9H).

A solution of 4N HCl/dioxane (1 mL) was added to a stirred solution of2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide(0.5 g, 1.1 mmol) in CH₂Cl₂ (10 mL). The resulting mixture was stirredat room temperature for 1 day. Ether (20 mL) was added and the mixturewas stirred for 2 h. The slurry was filtered and washed with ether toafford mixture isomers of2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-hydroxy-propionamidehydrochloride (0.4 g, 78%) as white solid: mp 151-153° C.; ¹H NMR(DMSO-d₆) δ 9.89 (9.94) (s, 1H), 8.31 (b, 3H), 7.98-7.95 (m, 1H),7.39-7.16 (m, 2H), 6.68 (6.65) (s, 2H), 6.12 (6.25) (s, 1H), 5.63 (b,1H), 4.18 (b, 1H), 3.91 (d, J=8 Hz, 2H), 3.87-3.70 (m, 12H); ¹³C NMR(DMSO-d₆) δ 166.20, 161.24 (160.99), 152.62, 151.52 (150.82), 139.43(138.36), 133.54 (132.24), 129.80 (128.56), 126.60 (126.29), 126.16(125.31), 122.99 (122.32),118.51 (118.47), 111.50 (111.16), 106.91(106.26), 94.46 (93.64), 66.33, 60.33 (60.15), 56.15, 56.02, 54.43; AnalCalcd for C₂₂H₂₆N₃O₆Cl+0.2H₂O: C, 56.52; H, 5.69; N, 8.99; Cl, 7.58.Found: C, 56.29; H, 5.81; N, 8.63; Cl, 7.35.

4.6.2.343-(3,4-Bis-difluoromethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile(E and Z isomers)

n-Butyl lithium (2.5 M, 3.7 mL) was added to s stirred solution of3,5-dimethoxy-bromobenzene (2.0 g, 9.2 mmol) in THF (15 mL) at −65° C.After stirring for 30 min, a solution of3,4-bis-difluoromethoxy-benzaldehyde (2.0 g, 8.4 mmol) in THF (15 mL)was added slowly. The resulting mixture was stirred at −65° C. for 6 hand then quenched with isopropanol (5 mL). Water (40 mL) was added andthe mixture was extracted with ether (3×60 mL). The combined organiclayers were washed with water (2×40 mL), brine (40 mL), and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (Silica gel, Hexane: EtOAc 7: 3) to afford(3,4-bis-difluoromethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol (1.3 g,42%): ¹H NMR (CDCl₃) δ 7.32 (m, 1H), 7.19 (m, 2H), 6.86-6.19 (m 5H),5.69 (d, J=2 Hz, 1H), 3.76 (s, 6H), 2.47 (d, J=2 Hz, 1H).

A mixture of3-(3,4-bis-difluoro-phenyl)-3-(3,5-dimethoxy-phenyl)-methanol (1.3 g,3.3 mmol) and MnO₂ (2.3 g, 30 mmol) in CH₂Cl₂ (50 mL) was stirred atroom temperature for 3 days. The mixture was filtered through Celite andthe filtrate was concentrated. The crude product was purified by flashchromatography (Silica gel, Hexane: EtOAc 8: 2) to afford(3,4-bis-difluoromethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone (0.9g, 76%): ¹H NMR (CDCl₃) δ 7.75-7.68 (m, 2H), 7.36 (d, J=8 Hz, 1H), 6.88(d, J=2 Hz, 2H), 6.69 (t, J=1 Hz, 1H), 6.63 (t, J=72 Hz, 1H), 6.59 (t,J=73 Hz, 1H), 3.80 (s, 6H).

Lithium bis-(trimethylsilyl)amide (1M, 3.0 mL) was added dropwise to astirred solution of diethyl cyanomethylphosphate (0.5 g, 3.0 mmol) inTHF (10 mL) at 5-8° C. The mixture was stirred at room temperature for40 min. A solution of(3,4-bis-difluoromethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone (0.9g, 2.5 mmol) in THF (20 mL) was added and the mixture was stirred atroom temperature for 17 h. The resulting mixture was poured into icewater (100 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were washed with water (2×40 mL), brine (40 mL) and dried(MgSO₄). Solvent was removed and the residue was purified by flashchromatography (Silica gel, Hexane: CH₂Cl₂ 4: 6) to afford a mixture ofisomers of3-(3,4-bis-difluoromethxoy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile(0.6 g, 59%) as a white solid: mp 60-62° C.; ¹H NMR (CDCl₃) δ 7.35-7.22(m, 3H), 6.90-6.20 (m, 5H), 5.76 (5.70) (s, 1H), 3.77 (3.80) (s, 6H);¹³C NMR (CDCl₃) δ 160.98 (160.90), 160.65 (160.55), 143.60 (141.87),139.92, 137.78 (137.06), 135.13, 127.99 (126.83), 123.70 (122.75),121.84 (121.78), 117.25 (117.05), 115.68 (t, J=1047 Hz), 115.58 (t,J=1047 Hz), 106.80 (107.56), 102.51 (102.37), 96.29 (96.24); Anal Calcdfor C₁₉H₁₅NO₄F₄: C, 75.44; H, 3.81; N, 3.53; F, 19.13. Found: C, 57.82;H, 3.61; N, 3.38; F, 19.39.

4.6.2.352-Amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxyphenyl}-acetamidehydrochloride (E and Z isomers)

N-BOC-glycine (0.6 g, 3.5 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (0.9g, 2.9 mmol), dicyclohexylcarbodiimide (0.7 g, 3.5 mmol) and1-hydroxbenzotriazole (0.6 g, 4.3 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (20 mL) was addedand the mixture was filtered. The filtrate was diluted with EtOAc (50ml) and washed with water (3×30 mL), brine (2×30 mL) and dried (MgSO₄).Solvent was removed and the residue was purified by flash chromatography(Silica gel, CH₂Cl₂: EtOAc 9: 1) to afford a mixture of isomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,5-dimethox-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(1.2 g, 89%): ¹H NMR (CDCl₃) δ 8.52-8.36 (m, 2H), 7.27-6.83 (m, 2H),6.53-6.41 (m, 3H), 5.64 (5.70) (s, 1H), 5.20 (b, 1H), 3.95-3.90 (m, 5H),3.75 (3.79) (s, 6H), 1.48 (s, 9H).

A solution of 2N HCl/ether (5 mL) was added to a stirred solution ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(1.2 g, 2.6 mmol) in CH₂Cl₂ (25 mL). The solution was stirred overnight.Ether (35 mL) was added and the mixture was stirred for 2 h. The slurrywas filtered and washed with ether to afford a mixture of isomers of2-amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamidehydrochloride (0.9 g, 81%) as a white solid: mp 167-169° C.; ¹H NMR(DMSO-d₆) δ 9.94 (9.89) (s, 1H), 8.28 (b, 3H), 8.00 (7.89) (d, J=1 Hz,1H), 7.39-7.15 (m, 2H), 6.62 (t, J=2 Hz, 1H), 6.48 (d, J=2 Hz, 2H), 6.25(6.18) (s, 1H), 3.94-3.73 (m, 11H); ¹³C NMR(DMSO-d₆) δ 165.34, 161.05(161.11), 160.35 (160.31), 150.62 (151.53), 140.26(139.04),128.69(128.58), 126.30(126.25), 124.92(124.32), 122.48(122.11), 118.22(118.16), 111.21 (111.57), 106.71 (107.13), 101.96 (101.18), 95.49(94.20), 55.98 (56.07), 55.39, 40.96 (40.89); Anal Calcd forC₂₀H₂₂N₃O₄Cl+0.3H₂O: C, 58.69; H, 5.57; N, 10.27; Cl, 8.66. Found: C,58.43; H, 5.17; N, 10.50; Cl, 8.62.

4.6.2.362-Amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamidehydrochloride (E and Z isomers)

N-BOC-L-Alanine (0.7 g, 3.9 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (1.0g, 3.2 mmol), dicyclohexylcarbodiimide (0.8 g, 3.9 mmol) and1-hydroxybenzotriazole (0.7 g, 4.8 mmol) in DMF (15 mL). The mixture wasstirred at room temperature for 2 days. Ethyl acetate (20 mL) and themixture was filtered. The filtrate was diluted with EtOAc (50 mL) andwashed with water (3×30 mL), brine (2×30 mL) and dried (MgSO₄). Solventwas removed and the residue was purified by flash chromatography (Silicagel, CH₂Cl₂: EtOAc 9: 1) to afford a mixture of isomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(1.2 g, 79%): ¹H NMR (CDCl₃) δ 8.56-8.52 (m, 1H), 8.39 (s, 1H),7.32-6.82 (m, 2H), 6.53-6.42 (m, 3H), 5.64 (5.71) (s, 1H), 5.00 (b, 1H),4.32 (b, 1H), 3.93 (3.90) (s, 3H), 3.73 (3.79) (s, 6H), 1.47 (s, 9H),1.43 (d, J=6 Hz, 3H).

A solution of 2N HCl/ether (5.0 mL) was added to a stirred solution ofN-BOC-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(1.2 g, 2.5 mmol) in CH₂Cl₂ (20 mL). The mixture was stirred at roomtemperature for 2 days. Ether (30 mL) was added and the mixture wasstirred for 2 h. The slurry was filtered and was washed with ether toafford a mixture of isomers of2-amino-N-{5-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamidehydrochloride (0.8 g, 80%) as a white solid: mp231-233° C.; ¹H NMR(DMSO-d₆) δ 9.97 (9.92) (s, 1H), 8.40 (b, 3H), 7.91 (7.86) (d, J=2 Hz,1H), 7.38-7.15 (m, 2H), 6.64 (t, J=2 Hz, 1H), 6.48 (d, J=2 Hz, 2H), 6.26(6.19) (s, 1H), 4.25-4.16 (q, J=6 Hz, 1H), 3.94 (3.90) (s, 3H), 3.76(3.74) (s, 6H), 1.42 (1.40) (d, J=6 Hz, 3H); ¹³C NMR (DMSO-d₆) δ 168.85,160.99, 160.36 (160.32), 151.12 (151.89), 140.21 (139.01), 128.65(129.55), 126.22 (126.25), 125.33 (126.13), 123.08 (122.54), 118.20(118.16), 111.28 (111.60), 106.70 (107.16), 102.00 (101.22),95.56(94.23), 56.12 (56.03), 55.39, 48.60 (53.67), 17.40; Anal Calcd forC₂₁H₂₄N₃O₄Cl+0.2H₂O: C, 59.84; H, 5.83; N, 9.97; Cl, 8.41. Found: C,59.54; H, 5.62; N, 10.37; Cl 8.41.

4.6.2.373-(4-Amino-3-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(E and Z isomers)

(3-Methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol wasprepared analogously to(4-methoxy-3-nitro-phenyl)-(3,4,5-trimthoxy-phenyl)-methanol using3,4,5-trimethoxy-bromobenzene (3.0 g, 12.1 mmol), magnesium turning (1.0g, 24.3 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.8 g, 10.1 mmol). Thecrude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford(3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g,60%): ¹H NMR (CDCl₃) δ 7.82 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8Hz, 1H), 6,54 (s, 2H), 5,76 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.85(s, 9H).

A suspension of(3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g,6.1 mmol) and MnO₂ (6.0 g, 69 mmol) in CH₂Cl₂ (100 mL) was stirred atroom temperature for 2 days. The mixture was filtered through Celite andthe filtrate was concentrated. The crude product was purified by flashchromatography (silica gel, Hexane: EtOAc 7:3) to afford(3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (1.0 g,48%): ¹H NMR (CDCl₃) δ 7.90 (d, J=8 Hz, 1H), 7.50 (d, J=0 Hz, 1H), 7.37(d, J=6 Hz, 1H), 7.05 (s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.88 (s, 6H).

3-(3-Methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(E and Z isomers) were prepared analogously to3-(4-methoxy-3-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone(1.2 g, 3.5 mmol), lithium bis(trimethylsilyl)amide (3.9 ml, 3.9 mmol)and diethyl cyanomethylphosphate (0.7 g, 3.9 mmol). The crude productwas purified by flash chromatography (silica gel, CH₂Cl₂) to affordmixture isomers of3-(3-methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.9 g, 70%): ¹H NMR (CDCl₃) δ 7.93 (dd, J=8.4 and 6 Hz, 1H), 7.06-6.96(m, 2H), 6.65 (s, 1H), 6.46 (s, 2H), 5.80(5.71) (s, 1H), 4.00-3.81 (m,12H).

A suspension of3-(3-methoxy-4-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.9 g, 2.4 mmol) and tin chloride dihydrate (4.0 g, 17.7 mmol) inethanol (25 mL) was heated at 70° C. for 1 h. The mixture was cooled andpoured into ice (200 mL). The pH was made strongly alkaline by theaddition of ION NaOH. The mixture was extracted with EtOAc (5×50 mL) andthe combined organic extracts were washed with water (40 mL), brine (40mL), and dried (MgSO₄). Solvent was removed and the residue was purifiedby flash chromatography (silica gel, Hexane: EtOAc 1:1) to affordmixture isomers of3-(4-amino-3-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile(0.4 g, 42%) as a yellow solid: mp 123-125° C.; ¹H NMR (CDCl₃) δ7.05-6.53 (m, 5H), 5.56(5.43) (s, 1H), 4.12 (s, 2H), 3.91-3.81 (m, 12H);¹³C NMR (CDCl₃) δ 163.19, 163.09, 152.99, 152.93, 146.63, 139.82,138.74, 135.43, 132.66, 128.33, 126.35, 124.12, 118.96, 113.76, 113.74,111.99, 110.22, 107.35, 106.42, 91.14, 90.52, 60.94, 56.28, 56.25,55.74, 55.59; Anal Calcd for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N, 8.23.Found: c, 66.92; H, 5.76; N, 8.10.

4.6.2.38 3,3-Bis-(3,4,5-trimethoxy-phenyl)-acrylonitrile

Bis-(3,4,5-trimethoxy-phenyl)-methanone (0.32 g, 0.88 mmol),cyanomethylphosphonic acid diethyl ester (0.28 ml, 0.31 mmol) inanhydrous THF (20 ml), and potassium bis(trimethylsilyl)amide (0.35 g,1.8 mmol) were treated in the same manner as described above for thesynthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified via flash column chromatography to give3,3-Bis-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (0.25 g,74%): mp, 146-148° C.; ¹HNMR (DMSO-d₆) δ 6.69 (d, J=5 Hz, 4H, Ar), 6.32(s, 1H, CH), 3.77-3.72 (m, 18H, 60CH₃); ¹³C NMR (DMSO-d₆) δ 161.27,152.69, 152.61, 139.60, 138.66, 133.06, 131.94, 118.43, 107.09, 106.23,100.40, 95.21, 60.13, 60.10, 56.08, 56.07; Anal. Calcd. For C₂₁H₂₄NO₆:C, 65.44; H, 6.02; N, 3.63. Found: C, 65.08; H, 5.99; N, 3.45.

4.6.2.392-[(3,5-Dimethoxy-phenyl)-(3-methoxy-phenyl)-methylenel-malononitrile

(3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (0.31 g, 1.12 mmol),malononitrile (0.08 ml, 1.23 mmol), and aluminum oxide (0.57 g, 5.6mmol) were mixed and heated in an oil bath at 160° C. overnight. Aftercooling down to r.t., the brown mixture was extracted with CH₂Cl₂ (50ml), filtered through a Celite pad and concentrated to an oil, which waspurified via flash column chromatography (5% EtOAc in hexane gradient to20% EtOAc in hexane in about 40 min.) and lyophilized to give2-[(3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)-methylene]-malononitrile asa greenish solid (0.12 g, 34%): mp, 100-102° C.; ¹HNMR (DMSO-d₆) δ 7.47(t, J=8 Hz, 1H, Ar), 7.22 (dd, J=2.36, 8 Hz, 1H, Ar), 7.16 (t, J=1 Hz,1H, Ar), 6.96 (d, J=7 Hz, 1H, Ar), 6.78 (t, J=2 Hz, 1H, Ar), 6.62 (d,J=2 Hz, 2H, Ar), 3.79 (s, 3H, OCH₃), 3.76 (s, 6H, 20CH₃); ¹³C NMR(DMSO-d₆) δ 173.4, 160.3, 158.9, 137.5, 136.8, 130.1, 122.4, 118.0,115.3, 114.1, 114.0, 108.1, 103.6, 82.9, 55.6, 55.5; Anal. Calcd. ForC₁₉H₁₆N₂O₃: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.10; H, 4.87; N,8.59.

4.6.2.40 3-(3,5-Dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile

3-(3-Benzyloxyphenyl)-3-(3,5-dimethoxyphenyl)acrylonitrile (3.45 g), 20%palladium hydroxide on charcoal (0.103 g, 3% w.t.), cyclohexene (12 ml),and ethanol (24 ml) were heated to reflux overnight. The blacksuspension was cooled, filtered through a Celite pad, and concentratedto an oil, which was purified via flash column chromatography (5% EtOAcin hexane gradient to 30% EtOAc in hexane in about 30 min.) to give3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile as anoff-white solid (1.66 g, 64%): mp, 127-129° C.; ¹HNMR (DMSO-d₆) δ 9.73(s, 0.67H, OH of one isomer), 9.65 (s, 0.26H, OH of the other isomer),7.33-7.23 (m, 1H, Ar), 6.92-6.62 (m, 4H, Ar), 6.46 (d, J=2 Hz, 2H, Ar),6.32 (s, 0.73H, double bond proton of one isomer), 6.27 (s, 0.27H,double bond proton of the other isomer), 3.77 (s, 1.85H, 20CH₃ of oneisomer), 3.73 (s, 4.29H, 20CH₃ of the other isomer), isomer ratio27.6%:72.4%; ¹³C NMR (DMSO-d₆) δ 161.5, 160.4, 157.4, 157.2, 139.9,138.7, 138.1, 129.7, 119.7, 118.7, 118.0, 117.5, 116.7, 115.7, 115.0,107.1, 106.6, 101.8, 101.0, 96.3, 96.0, 55.4; Anal. Calcd. ForC₁₇H₁₅NO₃: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.40; H, 5.26; N,4.85.

4.6.2.41 3-(3,5-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile

Aluminum chloride (2.20 g, 16.5 mmol) was added to a stirred mixture ofanisole (1.63 ml, 15.0 mmol) in anhydrous methylene chloride (20 ml) inan ice bath. Then a solution of 3,5-dimethoxybenzoyl chloride (3.01 g,15.0 mmol) in anhydrous methylene chloride (10 ml) was added. Themixture was allowed to warm up to rt, then refluxed overnight. Aftercooling down to rt, the mixture was poured to ice water (50 ml), stirredfor 20 min., and extracted with methylene chloride (3×50 ml). Thecombined organic extracts were washed with sat. NaHCO₃ (3×50 ml), H₂O(2×50 ml), brine (50 ml), dried over MgSO₄, filtered and concentrated invacuo to an oil, which was purified via flash column chromatography (10%EtOAc in hexane) to give(3,5-dimethoxy-phenyl)-(4-methoxy-phenyl)-methanone as a yellow solid(3.11 g, 76%): mp, 90-920C; ¹HNMR (CDCl₃) δ 7.85 (d, J=8.0 Hz, 2H, Ar),6.96 (d, J=9.0 Hz, 2H, Ar), 6.88 (d, J=2.3 Hz, 2H, Ar), 6.65 (d, J=2.4Hz, 1H, Ar), 3.89 (s, 3H, OCH₃), 3.83 (s, 6H, 20CH₃). The product wascarried over to the next step.

To a stirred solution of cyanomethylphosphonic acid diethyl ester (2.15ml, 13.66 mmol) in anhydrous THF (10 ml) in an ice bath was addedlithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.66 ml, 13.66mmol) slowly. The mixture was stirred in rt for 40 min. To the mixture,a solution of (3,5-dimethoxyphenyl)-(4-methoxyphenyl)methanone(5193-23-B, 1.86 g, 6.83 mmol) in anhydrous THF (20 ml) was added. Themixture was refluxed overnight. The solution was poured into ice water(20 ml) and the two phases were separated. The THF phase was evaporatedand combined with the aqueous phase, which were then extracted withCH₂Cl₂ (2×40 ml), washed with water (50 ml), dried over MgSO₄, filteredand concentrated in vacuo to an oil, which was purified via flash columnchromatography (20% EtOAc in hexane) to give3-(3,5-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellowoil which was solidified slowly (1.97 g, 98%): mp, 79-81° C.; ¹HNMR(DMSO-d₆) δ 7.35-7.31 (m, 2H, Ar), 7.07-6.96 (m, 2H, Ar), 6.65-6.62 (m,1H, Ar), 6.46-6.44 (m, 2H, Ar), 6.23 (s, 0.43H, double bond H of oneisomer), 6.20 (s, 0.58H, double bond H of the other isomer),3.82-3.68(multiple singlets, 9H, OCH₃); ¹³C NMR (CDCl₃) δ 162.8, 162.6, 161.7,161.3, 160.9, 160.8, 141.7, 139.2, 131.5, 131.0, 130.1, 129.3, 118.4,118.2, 114.2, 114.0, 107.8, 107.2, 102.2, 102.1, 93.8, 93.0, 55.6, 55.5,55.5;

Anal. Calcd. for C₁₈H₁₇NO₃+0.05H₂O: C, 72.92; H, 5.89; N, 4.65. Found:C, 72.90; H, 5.52; N, 4.67.

4.6.2.42 3,3-Bis-(4-methoxy-phenyl)-acrylonitrile

Bis-(4-methoxy-phenyl)-methanone (2.42 g, 10 mmol),cyano-methylphosphonic acid diethyl ester (1.6 ml, 10 mmol) in anhydrousTHF (10 ml), and sodium hydride (0.48 g, 10 mmol) were treated in thesame manner as described above for the synthesis of3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile.The crude material was purified by flash column chromatography to give3,3-bis-(4-methoxy-phenyl)-acrylonitrile as a solid (1.84 g, 69%): ¹HNMR (CDCl₃) δ 7.39 (d, J=8.7 Hz, 1H, Ar), 7.25 (d, J=8.7 Hz, 1H, Ar),6.95 (d,j=8.7 Hz, 1H, Ar), 6.88 (d, J=8.7 Hz, 1H, Ar), 5.54 (s, 1H, CH),3.86, 3.83 (2s, 6H, CH₃); ¹³C NMR (CDCl₃) δ 162.3, 161.4, 160.9, 131.7,131.3, 130.1, 129.5, 118.7, 113.9, 113.8, 91.5, 55.4, 55.3; Anal. Calcd.For C₁₇H₁₅NO₂: C, 76.94; H, 5.70; N, 5.27. Found: C, 76.83; H, 5.64; N,5.17.

4.6.2.43N-{4-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-phenyl}acetamide

A mixture of 3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.7 g, 3.2mmol), N-(4-iodo-phenyl)-acetamide (1.4 g, 5.4 mmol), NaHCO₃ (1.1 g,12.8 mmol), Bu₄NBr (1.2 g, 3.6 mmol) and Pd(OAc)₂ (0.04 g, 0.2 mmol) inDMF (15 mL) was heated at 70° C. for 2 days. The cooled mixture waspoured into water (150 mL) and was extracted with EtOAc (3×50 mL). Thecombined organic extracts were washed with water (2×50 mL), brine (50mL) and dried (MgSO₄). Solvent was removed and the residue was purifiedby flash chromatography (silica gel, CH₂Cl₂: EtOAc 9:1) to affordN-{4-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-phenyl}acetamide (0.4g, 32%): mp 175-177° C.; ¹H NMR (CDCl₃) δ 7.51(d, J=8 Hz, 2H), 7.41 (s,1H), 7.26 (d, J=9.0 Hz, 2H), 7.02-6.89 (m, 3H), 5.57 (s, 1H), 4.11-4.03(q, J=7 Hz, 2H), 3.92 (s, 3H), 2.19 (s, 3H), 1.44 (t, J=7 Hz, 3H); ¹³CNMR (CDCl₃) δ 168.38, 162.14, 150.93, 147.96, 139.91, 134.84, 129.58,129.30, 123.08, 119.34, 118.53, 114.06, 111.01, 92.49, 64.53, 55.96,24.65, 14.66; Anal Calcd for C₂₀H₂₀N₂O₃: C, 71.46; H, 5.99; N, 8.33.Found: C, 71.46, 6.01; N, 8.25.

4.6.2.44N-{5-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(E and Z isomers)

N-{5-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(E and Z isomers) were prepared analogously toN-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamideusing3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(0.4 g, 1.1 mmol) and acetyl chloride (1.1 mL). The crude product wasslurried with hexane to giveN-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide(0.2 g, 41%) as a white solid: mp 155-157° C.; ¹H NMR (CDCl₃) δ 9.25 (d,J=2 Hz, 1H), 7.90 (d, 13.5 Hz, 1H), 7.17-6.90 (m, 3H), 6.75 (d, J=1 Hz,1H), 6.13 (s, 1H), 5.97 (s, 1H), 4.02-3.97 (m, 2H), 3.94-3.97 (m, 6H),2.07 (d, J=7 Hz, 3H), 1.70 (t, 3H); ¹³C NMR (CDCl₃) δ 161.29, 151.18,150.02, 147.76, 147.32, 130.47, 130.23, 129.18, 128.91, 127.26, 127.22,122.40, 122.18, 118.77, 118.70, 113.81, 122.20, 111.43, 111.34, 111.04,110.77, 92.73, 92.45, 63.76, 63.71, 55.87, 55.41, 23.80, 23.68, 14.57;Anal Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.94,5.93; N, 7.53.

4.6.2.453-(3-Ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-Pyrrol-1-yl-phenyl)-acrylonitrile(E and Z isomers)

2,5-Dimethoxytetrahydrofuran (0.2 g, 1.7 mmol) was added to a stirredsolution of3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(0.5 g, 1.5 mmol) in acetic acid (10 mL). The reaction mixture washeated to reflux under nitrogen for one hour. The mixture was cooleddown to room temperature. The mixture was stirred with EtOAc (100 mL)and saturated NaHCO₃ (40 mL) was added slowly. The EtOAc solution waswashed with water (60 mL), brine (60 mL) and dried (MgSO₄). Solvent wasremoved and the residue was purified by flash chromatography (silicagel, Hexane: EtOAc 6:4) to afford mixture of isomers of3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-pyrrol-1-yl-phenyl)-acronitrile(0.4 g, 60%) as a white solid: mp 109-11 1° C.; ¹H NMR (CDCl₃) δ 7.00(m, 2H), 7.47-6.81 (m, 6H), 6.30 (m, 2H), 5.59 (5.57) (s, 1H), 4.05 (m,2H), 3.91 (m, 6H), 1.45 (m, 3H); ¹³C NMR (CDCl₃) δ 161.67(161.61),153.93(154.35), 151.56(151.00), 148.27(148.00), 131.40(132.10),129.83(130.06), 129.03(127.16), 125.93(127.93), 123.07, 122.21,122.05(121.93), 118.52(118.43), 114.00, 112.01(112.06), 111.09(112.70),109.15(109.28), 92.45, 64.56, 56.05(56.00), 14.69; Anal. Calcd forC₂₃H₂₂N₂O₃. Theoretical: C, 73.78; H, 5.92, N, 7.48. Found: C, 73.46; H,5.71; N, 7.35.

4.6.2.462-Amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamideHydrochloride (E and Z isomers)

N-BOC-L-Alanine (1.1 g, 5.6 mmol) was added to a stirred solution of3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(1.5 g, 4.6 mmol), dicyclohexyl carbodiimide (1.1 g, 5.6 mmol) and1-hydroxybenzotriazole (0.9 g, 6.9 mmol) in DMF (30 mL). The mixture wasstirred at room temperature for one day. Ethyl acetate (40 mL) was addedand the mixture was filtered. The filtrate was diluted with ethylacetate (50 mL) and washed with water (3×30 mL), brine (2×30 mL) anddried (MgSO₄). Solvent was removed and the residue was purified by flashchromatography (silica gel, CH₂Cl₂: EtOAc 9:1) to afford a mixture ofisomers ofN-BOC-2-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(2.3 g, 98%): ¹H NMR (CDCl₃) δ 8.52 (d, 1H), 8.37-7.23 (m, 6H), 5.58 (d,1H), 5.00 (b, 1H), 4.33 (b, 1H), 4.04 (m, 2H), 3.91 (q, 6H), 1.40-1.47(m, 15H).

A solution of 2N HCl/ether (8.8 mL) was added to a stirred solution ofN-BOC-2-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamide(2.1 g, 4.4 mmol) in CH₂Cl₂ (50 mL). The mixture was stirred at roomtemperature for 2 days. Ether (90 mL) was added and the mixture wasstirred for 2 hours. The slurry was filtered and was washed with etherto afford a mixture of isomers of2-amino-N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-propionamidehydrochloride (1.4 g, 74%) as a white solid: mp 207-209° C.; ¹H NMR(DMSO-d₆) δ 9.94(9.90) (s, 1H), 8.31 (b, 1H), 7.92-6.75 (m, 6H),6.16(6.02) (s, 1H), 4.19 (m, 1H), 3.99 (m, 2H), 3.94(3.91) (s, 3H),3.79(3.83) (s, 3H), 1.41 (d, 3H), 1.31 (t, 3H); ¹³C NMR (DMSO-d₆) δ168.81 161.04(161.31), 151.86(150.18), 151.06(150.94), 147.80(147.36),130.48(130.43), 129.07(129.19), 126.61(125.64), 126.11, 123.09(122.88),122.23(122.40), 118.69(118.75), 112.25(113.78), 114.48(111.55),111.36(111.26), 93.02(92.85), 63.81(63.76), 56.04(56.13), 55.59(55.52),48.62, 17.42, 14.62(14.59); Anal. Calcd for C₂₂H₂₆N₃O₄Cl+0.03H₂O;Theoretical: C, 61.10; H, 6.07; N, 9.72; Cl, 8.20. Found: C, 60.75; H,5.84; N, 9.51; Cl, 8.33.

4.6.2.47 3-(3,5-Dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile

A solution of 1-bromo-3-methoxybenzene (2.48 g, 13.24 mmol) in anhydrousTHF (10 ml) was cooled to −78° C., evacuated and refilled with nitrogenfor ten cycles. To this clear solution was slowly added n-butyl lithium(5.30 ml, 13.24 mmol) and stirred for 30 min. Then a solution of3,5-dimethoxybenzaldehyde (2.00 g, 12.04 mmol) in anhydrous THF (10 ml)was added via a syringe. The mixture was stirred at −78° C. undernitrogen for 4 h then quenched with 2-propanol (2.1 ml, 27 mmol) andstirred overnight. To the orange colored mixture was added 30 ml ofwater and extracted with ether (3×60 ml). The combined ether extractswas washed with water (2×60 ml), dried over MgSO₄, filtered andconcentrated in vacuo to an oil, which was purified via flash columnchromatography to give(3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)-methanol as an off-white oil(2.69 g, 82%), HPLC purity was 98.3% at 2.81 min. (50/50 ACN/0.1%H₃PO₄): ¹HNMR (CDCl₃) δ 7.26-7.29 (m, 1H, Ar), 6.95-6.92 (m, 2H, Ar),6.81-6.77 (m, 1H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.34 (t, J=2 Hz, 1H),5.68 (d, J=3 Hz, 1H, CH), 3.77 (s, 3H, single OCH₃ group), 3.74 (s, 6H,20CH₃ groups), 2.45 (d, J=3 Hz, 1H, OH). The product was carried over tothe next step.

To a stirred solution of (3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanol(2.47 g, 9.0 mmol) in CH₂Cl₂ (20 ml) at rt was added activated MnO₂powder (3.91 g, 45 mmol) and kept adding 2˜3 equivalents of MnO₂ every3˜5 h until HPLC showed at least 98% conversion occurred. The blacksuspension was filtered through a Celite pad, concentrated in vacuo togive (3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)methanone was an oil (2.35g, 92%): ¹HNMR (CDCl₃) δ 7.38-7.35 (m, 3H, Ar), 7.15-7.13 (m, 1H, Ar),6.93 (d, J=2 Hz, 2H, Ar), 6.67 (t, J=2 Hz, 1H, Ar), 3.86 (s, 3H, singleOCH₃ group), 3.83 (s, 6H, 20CH₃), 0.99 (s, 9H, 30CH₃). The product wascarried over to the next step.

To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.18ml, 7.49 mmol) in anhydrous THF (10 ml) in an ice bath was added lithiumbis(trimethylsilyl)amide (1.0 M solution in THF, 7.49 ml, 7.49 mmol)slowly. The mixture was stirred in rt for 40 min, before a solution of(3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (1.02 g, 3.75 mmol) inanhydrous THF (20 ml) was added. The mixture was refluxed overnight. Thesolution was poured into ice water (20 ml) and the two phases wereseparated. The THF phase was evaporated and combined with the aqueousphase, which were then extracted with CH₂Cl₂ (2×40 ml), washed withwater (50 ml), dried over MgSO₄, filtered and concentrated in vacuo toan oil, which was purified via flash column chromatography to give3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile as anoff-white solid (1.06 g, 96%): mp, 81-83° C.; ¹HNMR (DMSO-d₆) δ7.46-7.30 (m, 2H, Ar), 7.11-6.85 (m, 6H, Ar), 6.66-6.62 (m, 2H, Ar),6.47 (t, J=1 Hz, 4H, Ar), 6.39 (s, 1H, double bond proton of oneisomer), 6.38 (s, 1H, double bond proton of the other isomer), 3.78-3.73(multiple singlets, 18H, 60CH₃), isomer ratio based on ¹HNMR close to48%:52%; ¹³C NMR (CDCl₃) δ 163.0, 163.0, 160.9, 160.8, 159.8, 159.6,141.0, 140.1, 138.8, 138.2, 129.8, 129.7, 122.1, 121.0, 117.8, 117.8,116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 122.1, 122.1, 121.0,117.8, 117.8, 116.1, 115.9, 115.0, 114.3, 107.8, 107.0, 102.3, 102.2,95.4, 95.4, 55.6, 55.6, 55.5; Anal. Calcd. For C₁₈H₁₇NO₃: C, 73.20; H,5.80; N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.

4.6.2.48 3-(3,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile

Aluminum chloride (2.15 g, 16.12 mmol) was added to a stirred mixture of1,2-dimethoxybenzene (2.03 g, 14.65 mmol) in anhydrous methylenechloride (20 ml) in an ice bath. Then a solution of 4-methoxybenzoylchloride (2.50 g, 14.65 mmol) in anhydrous methylene chloride (50 ml)was added. The mixture was allowed to warm up to rt, then refluxedovernight. After cooling down to rt, the mixture was poured to ice water(50 ml), stirred for 20 min., and extracted with methylene chloride(3×50 ml). The combined organic extracts were washed with sat. NaHCO₃(3×50 ml), H₂O (2×50 ml), brine (50 ml), dried over MgSO₄, filtered andconcentrated in vacuo to an oil, which was purified via flash columnchromatography (10% EtOAc in hexane) to give(3,4-dimethoxy-phenyl)-(4-methoxy-phenyl)methanone as an off-white solid(3.66 g, 92%); ¹HNMR (CDCl₃) δ 7.80 (d, J=8 Hz, 2H, Ar), 7.44 (d, J=1Hz, 12H, Ar), 7.37 (dd, J=1 Hz and 8 Hz, 1H, Ar), 6.97 (d, J=8 Hz, 2H,Ar), 6.90 (d, J=8 Hz, 1H), 3.96 (s, 3H, OCH₃), 3.94 (s, 3H, OCH₃), 3.89(s, 3H, OCH₃). The product was carried over to the next step.

(3,4-dimethoxyphenyl)-(4-methoxyphenyl)methanone (2.00 g, 7.35 mmol),cyanomethylphosphonic acid diethyl ester (2.31 ml, 14.69 mmol) inanhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 Msolution in THF, 14.69 ml, 14.69 mmol) were treated in the same manneras described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (5% EtOAc in hexanegradient to 30% EtOAc in hexane in about 40 min.) to give3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a pinkoil (2.08 g, 96%): ¹HNMR (DMSO-d₆) δ 7.34-6.7 (m, 7H, Ar), 6.14 (s,0.50H, double bond proton of one isomer), 6.08 (s, 0.45H, double bondproton of the other isomer), 3.83-3.73 (multiple singlets, 9H, 30CH₃);¹³C NMR(CDCl₃)δ 162.6, 162.5, 161.6, 161.2, 151.2, 150.7, 149.0, 148.8,132.2, 131.7, 131.5, 130.3, 129.8, 129.5, 123.2, 122.3, 118.8, 118.8,114.1, 114.0, 112.9, 111.5, 110.9, 91.9, 91.8, 56.2, 56.1, 56.1, 55.5,55.5; Anal. Calcd. For C₁₈H₁₇NO₃: C, 71.92; H, 6.19; N, 4.32 (+0.04H₂O).Found: C, 71.95; H, 6.04; N, 4.54.

4.6.2.493-(3,5-Dimethoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile

To a solution of 5-bromo-2-methoxyphenol (0.86 g, 4.24 mmol) in DMF (20ml) was added iodoethane (0.68 ml, 8.47 mmol), and Na₂CO₃ (0.90 g, 8.47mmol) at rt. The white suspension was stirred at 50° C. overnight. Water(100 ml) and EtOAc (100 ml) were poured into the mixture. The two phaseswere separated and the aqueous was extracted with EtOAc (2×50 ml). Thecombined organic phases were washed with water (100 ml), dried overMgSO₄ and concentrated to a clear oil, which quickly solidified to4-bromo-2-ethoxy-1-methoxy-benzene as an off-white solid (0.68 g, 69%):¹HNMR (CDCl₃) δ 7.04-6.97 (m, 2H, Ar), 6.74 (d, J=8 Hz, 1H, Ar), 4.07(q, J=7 Hz, 2H, CH₂CH₃), 3.85 (s, 3H, OCH₃), 1.47 (t, J=7 Hz, 3H,CH₂CH₃). The product was carried over to the next step.

4-bromo-2-ethoxy-1-methoxybenzene (0.66 g, 2.86 mmol), n-butyl lithium(1.14 ml, 2.86 mmol), and 3,5-dimethoxybenzaldehyde (0.43 g, 2.60 mmol)were treated in the same manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash colurn chromatography (20% EtOAc in hexanegradient to 50% EtOAc in hexane in about 40 min.) to give(3,5-dimethoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as anoff-white solid (0.66 g, 80%): ¹HNMR (CDCl₃)

6.92-6.80 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H,Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.07 (q, J=6 Hz, 2H, CH₂CH₃), 3.85 (s,3H, OCH₃), 3.76 (s, 6H, 20CH₃), 2.19 (d, J=3 Hz, 1H, OH), 1.44 (t, J=7Hz, 3H, CH₂CH₃). The product was carried over to the next step.

(3,5-dimethoxyphenyl)-(3-ethoxy-4-methoxyphenyl)methanol (0.65 g, 2.04mmol) and activated MnO₂ powder (1.4 g, 16 mmol) were treated in thesame manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The product(3,5-dimethoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone was an oil(0.65 g, 100%): ¹HNMR (CDCl₃) δ 7.49-7.39 (m, 2H, Ar), 6.91-6.87 (m, 3H,Ar), 6.65 (t, J=2 Hz, 1H, Ar), 4.17 (q, J=6 Hz, 2H, CH₂CH₃), 3.95 (s,3H, single OCH₃ group), 3.83 (s, 6H, 20CH₃), 1.50 (t, J=6 Hz, 3H,CH₂CH₃). The product was carried over to the next step.

(3,5-Dimethoxyphenyl)-(3-ethoxy-4-methoxyphenyl)methanone (0.63 g, 2.00mmol), cyanomethylphosphonic acid diethyl ester (0.63 ml, 3.98 mmol) inanhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 Msolution in THF, 3.98 ml, 3.98 mmol) were treated in the same manner asdescribed above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (5% EtOAc in hexanegradient to 40% EtOAc in hexane in about 40 min.) to give3-(3,5-dimethoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile asan off-white solid (0.60 g, 89%): mp, 110-112° C.; ¹HNMR (CDCl₃) δ7.04-6.82 (m, 3H, Ar), 6.55-6.43 (m, 3H, Ar), 5.65 (s, 0.50H, doublebond proton of one isomer), 5.43 (s, 0.5H, double bond proton of theother isomer), 4.13-3.99 (m, 2H, CH₂CH₃ from the two isomers), 3.92 &3.90 (s, 3H, single OCH₃ group from the two isomers), 3.80 & 3.77 (s,6H, 20CH₃ from the two isomers), 1.49-1.41 (two triplets, 3H, CH₂CH₃from the two isomers); ¹³C NMR (CDCl₃) δ 162.9, 162.8, 160.9, 160.8,151.7, 151.1, 148.3, 148.0, 141.6, 139.1, 131.2, 129.3, 123.3, 122.2,118.2, 114.2, 112.7, 111.2, 111.1, 107.8, 107.2, 102.3, 102.2, 93.8,93.2, 64.7, 56.2, 56.1, 55.7, 14.8; Anal. Calcd. For C₂₀H₂₁NO₄: C,70.78; H, 6.24; N, 4.13. Found: C, 70.62; H, 6.25; N, 4.01.

4.6.2.50 (3,4-Dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile

3-methoxybenzoyl chloride (2.06 ml, 14.65 mmol), 1,2-dimethoxybenzene(1.87 ml, 14.65 mmol) in anhydrous methylene chloride (25 ml), andaluminum chloride (2.15 g, 16.12 mmol) were treated in the same manneras described above for the synthesis of3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (20% EtOAc in hexane) togive (3,4-dimethoxy-phenyl)-(3-methoxy-phenyl)-methanone as a yellow oil(4.39 g, 100%); ¹HNMR (CDCl₃) δ 7.50 (d, J=1 Hz, 1H, Ar), 7.42-7.30 (m,4H, Ar), 7.14-7.09 (m, 1H, Ar), 6.90 (d, J=8 Hz, 1H, Ar), 3.96 (s, 3H,OCH₃), 3.95 (s, 6H, 20CH₃), 3.86 (s, 3H, OCH₃); ¹³C NMR (CDCl₃) δ 195.4,159.6, 153.1, 149.1, 139.7, 130.3, 129.2, 125.6, 122.5, 118.3, 114.4,112.3, 109.9, 56.2, 56.2, 55.6; Anal. Calcd. For C ₁₆H₁₆O₄: C, 70.58; H,5.92. Found: C, 70.38; H, 5.99; N, <0.05. The product was carried overto the next step.

(3,4-Dimethoxyphenyl)-(3-methoxyphenyl)methanone (CC-15126, 5193-25-B,2.00 g, 7.35 mmol), cyanomethylphosphonic acid diethyl ester (2.31 ml,14.69 mmol) in anhydrous THF (10 ml), and lithiumbis(trimethylsilyl)amide (1.0 M solution in THF, 14.69 ml, 14.69 mmol)were treated in the same manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (20% EtOAc in hexane) togive 3-(3,4-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile as apink oil (1.99 g, 92%): ¹HNMR (DMSO-d₆) δ 7.46-7.30 (m, 2H, Ar),7.14-7.04 (m, 4H, Ar), 6.98-6.84 (m, 7H, Ar), 6.72-6.68 (m, 1H, Ar),6.32 (s, 0.85H, double bond proton of one isomer), 6.20 (s, 0.97H,double bond proton of the other isomer), 3.83-3.73 (multiple singlets,18H, 60CH₃); ¹³C NMR (CDCl₃) δ 162.8, 162.7, 159.7, 159.6, 151.3, 150.8,149.0, 148.8, 140.9, 138.6, 131.5, 129.7, 129., 129.5, 123.4, 122.3,122.2, 121.3, 118.4, 118.2, 116.0, 115.9, 115.0, 114.5, 112.8, 111.2,110.9, 110.9, 93.8, 93.3, 56.2, 56.1, 56.1, 55.5; Anal. Calcd. ForC₁₈H₁₇NO₃: C, 72.20; H, 6.09; N, 4.43 (+0.04H₂O). Found: C, 72.33; H,6.10; N, 4.60.

4.6.2.51 3,3-Bis-(3-methoxy-phenyl)-acrylonitrile

3-methoxybenzaldehyde (2.20 ml, 18.08 mmol), 1-bromo-3-methoxybenzene(2.52 ml, 19.89 mmol), and n-butyl lithium (7.96 ml, 19.89 mmol) weretreated in the same manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in hexanegradient to 25% EtOAc in hexane in about 40 min.) to givebis-(3-methoxy-phenyl)-methanol as a light yellow oil (4.45 g, 100%):¹HNMR (CDCl₃)

7.28-7.21 (m, 2H, Ar), 6.96-6.94 (m, 4H, Ar), 6.82-6.78 (m, 2H, Ar),5.78 (d, J=3 Hz, 1H, CHOH), 3.78 (s, 6H, 2OCH₃ groups), 2.25 (d, J=3 Hz,1H, OH). The product was carried over to the next step.

Bis-(3-methoxyphenyl)methanol (4.67 g, 19.12 mmol) and activated MnO₂powder (5.7 g, 66 mmol) were treated in the same manner as describedabove for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The productbis-(3-methoxy-phenyl)-methanone was an oil (4.29 g, 92%): ¹HNMR (CDCl₃)

7.46-7.32 (m, 2H, Ar), 7.11-7.02 (m, 4H, Ar), 6.93-6.89 (m, 2H, Ar),5.83 (d, J=3 Hz, 1H, CHOH), 3.82 (s, 6H, 20CH₃ groups), 2.30 (d, J=3 Hz,1H, OH). The product was carried over to the next step.

Bis-(3-methoxyphenyl)methanone (1.23 g, 5.08 mmol),cyanomethylphosphonic acid diethyl ester (1.60 ml, 10.15 mmol) inanhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 Msolution in THF, 10.15 ml, 10.15 mmol) were treated in the same manneras described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in hexanegradient to 25% EtOAc in hexane) to give3,3-bis-(3-methoxy-phenyl)-acrylonitrile as a clear colorless oil (0.76g, 56%): ¹HNMR (DMSO-d₆) δ 7.47-7.30 (two triplets, 2H, Ar), 7.12-7.04(m, 2H, Ar), 6.98-6.82 (m, 4H, Ar), 6.38(s, 1H, double bond proton),3.78 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃); ¹³C NMR (CDCl₃) δ 163.0, 159.8,159.6, 140.3, 138.3, 129.8, 129.7, 122.1, 121.1, 117.9, 116.1, 115.9,115.0, 114.4, 95.3, 55.5; Anal. Calcd. For C₁₇H₁₅NO₂: C, 76.96; H, 5.70;N, 5.28. Found: C, 76.65; H, 5.72; N, 5.15.

4.6.2.52 4-[1-(3,5-dimethoxyphenyl)prop-1-enyl]-1,2-dimethoxybenzene

3,5-Dimethoxybenzoyl chloride (10.28 g, 51.24 mmol),1,2-dimethoxybenzene (6.53 ml, 51.24 mmol), and aluminum chloride (7.52g, 56.37 mmol) were treated in the same manner as described above forthe synthesis of3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in hexanegradient to 50% EtOAc in hexane in 50 min.) to give(3,4-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a lightyellow solid (11.14 g, 72%); 1 (DMSO-d₆) δ 7.38-7.33 (m, 2H, Ar), 7.09(d, J=8 Hz, 1H, Ar), 6.77 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 3.82 (s,3H, OCH₃), 3.79 (s, 6H, 20CH₃). The product was carried over to the nextstep.

(3,4-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.96 g, 3.18mmol), (ethyl)triphenylphosphonium bromide (2.36 g, 6.35 mmol), andlithium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.35 ml, 6.35mmol) were treated in the same manner as described above for thesynthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in hexanegradient to 20% EtOAc in hexane in about 30 min.) to give4-[1-(3,5-dimethoxyphenyl)prop-1-enyl]-1,2-dimethoxybenzene a lightbrown oil (0.97 g, 97%): ¹HNMR (CDCl₃) δ 6.89-6.83 (m, 2H, Ar),6.76-6.68 (m, 4H, Ar), 6.43-6.39 (m, 3H, Ar), 6.36-6.34 (m, 3H, Ar),6.20-6.03 (m, 2H, double bond protons), 3.91 (s, 3H, OCH₃), 3.86 (s, 3H,OCH₃), 3.83 (s, 6H, 20CH₃), 3.78 (s, 6H, 20CH₃), 3.74 (s, 6H, 20CH₃),1.78-1.74 (m, 6H, 2CH₃): ¹³C NMR (CDCl₃) δ 160.7, 160.6, 148.7, 148.7,148.3, 148.0, 145.4, 142.3, 142.3, 142.2, 135.6, 132.5, 124.4, 122.8,122.6, 119.9, 113.3, 111.0, 110.9, 110.3, 108.2, 105.8, 99.2, 99.0,56.0, 56.0, 55.5, 55.4, 15.9, 15.8; Anal. Calcd. For C₁₉H₂₂O₄: C, 72.59;H, 7.05. Found: C, 72.43; H, 6.96.

4.6.2.53 3-(3,4-Diethyl-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile

3,4-Dimethoxybenzoyl chloride (4.01 g, 20 mmol), 1,2-diethylbenzene(2.68 g, 20 mmol), and aluminum chloride (2.93 g, 22 mmol) were treatedin the same manner as described above for the synthesis of3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in hexanegradient to 20% EtOAc in hexane in 40 min.) to give(3,4-diethyl-phenyl)-(3,4-dimethoxy-phenyl)-methanone as an orange oil(2.45 g, 41%). The product was carried over without further purificationto the next step.

(3,4-Diethylphenyl)-(3,4-dimethoxyphenyl)methanone (2.45 g, 8.21 mmol),lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 18 ml, 18mmol), and cyanomethylphosphonic acid diethyl ester (2.8 ml, 18 mmol) inanhydrous THF (40 ml) were treated in the same manner as described abovefor the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (10% EtOAc in 1:1 mixtureof hexane and CH₂Cl₂) to give a light brown oil (2.72 g), which wasfurther purified via preparative HPLC to give3-(3,4-diethyl-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile as a whitesolid (0.34 g, 18%); mp, 129-131° C.: ¹HNMR (DMSO-d₆) 67.29 (d, J=7 Hz,1H, Ar), 7.18-7.10 (m, 3H, Ar), 6.97 (d, J=8 Hz, 1H, Ar), 6.71 (d, J=8Hz, 1H, Ar), 6.20 (s, 1H, double bond proton), 3.78 (s, 3H, OCH₃), 3.76(s, 3H, OCH₃), 2.73-2.61 (m, 4H, 2CH₂CH₃), 1.25 (m, broad, 6H, 2CH₂CH₃);¹³C NMR (DMSO-d₆) δ 161.6, 150.9, 148.6, 143.0, 141.4, 134.7, 130.5,129.0, 128.1, 126.9, 122.3, 118.7, 111.2, 111.0, 93.1, 55.6, 24.7, 24.6,15.1, 14.8; Anal. Calcd. For C₂₁H₂₃NO₂: C, 78.47; H, 7.21; N, 4.36.Found: C, 78.26; H, 7.27; N, 4.40.

4.6.2.5,4 3-(3,4-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acidmethyl ester

(3,4-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.50 g, 4.95mmol), (diethoxyphosphoryl)acetic acid methyl ester (2.29 g, 9.90 mmol),and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.90 ml,9.90 mmol) were treated in the same manner as described above for thesynthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudeyellowish oil was purified via preparative HPLC to give3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid methylester as a light yellow oil (0.45 g, 25%): ¹HNMR (CDCl₃) δ 6.89-6.72 (m,2H, Ar), 6.49-6.36 (m, 4H, Ar), 6.28 (s, 1H, double bond proton), 3.92(s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 3.75 (s, 6H, 20CH₃), 3.64 (s, 3H,OCH₃); Anal. Calcd. For C₂₀H₂₂O₆+1.06H₂O: C, 63.60; H, 6.45. Found: C,63.22; H, 5.88.

4.6.2.55 3-(3,4-Dimethoxy-phenyl)-3-(3,5-dimethoxy-Phenyl)-acrylic acid

(3,4-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.50 g, 4.95mmol), (diethoxyphosphoryl)acetic acid methyl ester (2.29 g, 9.90 mmol),and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.90 ml,9.90 mmol) were treated in the same manner as described above for thesynthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudeyellowish oil was purified via preparative HPLC to give3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid ethylester as a light yellow oil (0.79 g, 43%): ¹HNMR (CDCl₃) δ 6.89-6.72 (m,2H, Ar), 6.48-6.45 (m, 4H, Ar), 6.28 (s, 1H, double bond proton), 4.09(q, J=7 Hz, 2H, CH₂CH₃), 3.92 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 3.75(s, 6H, 20CH₃), 1.16 (t, J=7 Hz, 3H, CH₂CH₃). The product was carriedover to the next step.

3-(3,4-Dimethoxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester(0.76 g, 2.05 mmol), potassium hydroxide (5 N, 8.10 ml, 20.52 mmol),methanol (6 ml), and H₂O (1.5 ml) were mixed and stirred at rt for acouple of hours. The methanol was evaporated in vacuo leaving a clearsolution, which was extracted with ether (2×60 ml) to get rid of theimpurities. The aqueous phase was acidified with conc. HCl to pH around23 to form a white precipitation, which was extracted with CH₂Cl₂ (2×100ml), dried over MgSO₄, filtered and concentrated to give3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid as afoamy solid (0.69 g, 98%); mp, 90-920C: ¹HNMR (CDCl₃) δ 6.90-6.75 (m,4H, double bond protons and 2COOH), 6.50-6.24 (m, 12H, Ar), 3.92-3.75(multiple singlets, 24H, 80CH₃), isomer ratio based on ¹HNMR close to43%:57%; Anal. Calcd. For C₁₉H₂₀O₆: C, 66.27; H, 5.85. Found: C, 66.02;H, 5.81.

4.6.2.56 4-[1-(3,5-Dimethoxyphenyl)but-1-enyl]-1,2-dimethoxybenzene

(3,4-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.98 g, 6.54mmol), propyltriphenylphosphonium bromide (5.04 g, 13.08 mmol), andlithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.08 ml, 13.08mmol) were treated in the same manner as described above for thesynthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudeyellowish solid was purified via flash column chromatography (10% EtOAcin hexane) to give a light brown oil (2.72 g), which was furtherpurified via preparative HPLC to give4-[1-(3,5-dimethoxyphenyl)but-1-enyl]-1,2-dimethoxybenzene as acolorless oil (2.11 g, 98%): ¹HNMR (CDCl₃) δ 6.88-6.84 (m, 1H, Ar),6.76-6.67 (m, 2H, Ar), 6.43-6.33 (m, 3H, Ar), 6.08-5.94 (m, 1H, doublebond proton), 3.91-3.74 (multiple singlets, 12H, 40CH₃), 3.73 (s, 3H,OCH₃), 2.16-2.04 (m, 2H, CH₂CH₃), 1.04 (t, J=7 Hz, 3H, CH₂CH₃); ¹³C NMR(CDCl₃) δ 160.7, 160.6, 148.7, 148.4, 148.1, 145.3, 142.5, 140.8, 140.7,15.5, 132.8, 132.0, 130.3, 122.4, 120.0, 113.2, 110.9, 110.9, 110.3,108.0, 105.8, 99.2, 99.0, 56.0, 55.4, 23.4, 23.4, 14.8, 14.7; Anal.Calcd. For C₂₀H₂₄O₄: C, 73.15; H, 7.37. Found: C, 72.98; H, 7.25.

4.6.2.574-(3,4-Dimethoxy-phenyl)-4-(3,5-dimethoxy-phenyl)-but-3-en-2-one

A suspension of Pd(OAc)₂ (67 mg, 0.30 mmol) in DMF (1 ml) was added to astirred suspension of 4-(3,5-dimethoxyphenyl)-but-3-en-2-one (2.05 g,9.96 mmol), 4-bromo-1,2-dimethoxybenzene (2.15 ml, 14.94 mmol), NaOAc(1.39 g, 16.94 mmol), and tetrabutylammonium bromide (3.53 g, 10.96mmol) in DMF (19 ml). The suspension was heated at ˜60° C. overnight.The mixture was then poured into EtOAc (50 ml) and H₂O (150 ml),followed by extraction with EtOAc (2×50 ml), washing with H₂O (2×50 ml),brine (50 ml) and drying over MgSO₄. The crude was purified flash columnchromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane) togive 4-(3,4-dimethoxy-phenyl)-4-(3,5-dimethoxy-phenyl)-but-3-en-2-one asa gummy oil (0.49 g, 15%): ¹HNMR (CDCl₃) δ 6.93-6.92 (m, 1H, Ar),6.82-6.77 (m, 2H, Ar), 6.53-6.51 (m, 2H, Ar and double bond proton),6.38 (d, J=2 Hz, 2H, Ar), 3.87 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 3.79(s, 6H, 20CH₃), 1.91 (s, 3H, CH₃); ¹³C NMR (CDCl₃) δ 160.9, 153.8,150.7, 148.9, 141.1, 132.9, 126.5, 122.4, 113.2, 110.8, 100.9, 56.1,55.8, 55.6, 55.4, 30.0; Anal. Calcd. For C₂₀H₂₂O₅: C, 70.16; H, 6.48.Found: C, 70.26; H, 6.37; N, <0.05.

4.6.2.58 3-(3,4-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)propionitrile

A solution of3-(3,4-dimethoxyphenyl)-3-(3,5-dimethoxyphenyl)acrylonitrile (0.30 g,0.92 mmol) in EtOAc (10 ml) was added to a mixture of 10% palladium oncarbon (0.15 g, 50% w.t.) in EtOAc (20 ml). The mixture was thenhydrogenated on a Parr-Shaker overnight. The suspension was filteredthrough a Celite pad, washed with EtOAc, and the solvent was evaporatedto get an oil, which was further purified via flash columnchromatography to give a light brown oil which solidified into3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-propionitrile as anoff-white solid (0.20 g, 66%); mp, 121-123° C.: ¹HNMR (CDCl₃) δ 6.82 (d,J=2 Hz, 2H, Ar), 6.72 (s, wide, 1H, Ar), 6.36 (s, wide, 3H, Ar), 4.24(t, J=7 Hz, 1H, CHCH₂), 3.86 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 3.76 (s,6H, 20CH₃), 2.98 (d, J=7 Hz, 2H, CHCH₂); ¹³C NMR (CDCl₃) δ 161.2, 149.3,148.5, 144.0, 133.6, 119.5, 118.6, 111.5, 111.3, 106.1, 98.8, 56.1,56.1, 55.5, 47.0, 24.5; Anal. Calcd. For C₁₉H₂₁NO₄: C, 69.71; H, 6.47;N, 4.28. Found: C, 69.66; H, 6.42; N, 4.20.

4.6.2.593-(3,5-Dimethoxy-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-acrylonitrile

To a solution of 4-bromo-2-methoxyphenol (2.87 g, 14.13 mmol) in DMF (20ml) was added ethyldiisopropylamine (6.15 ml, 35.32 mmol). The clearsolution was stirred for 5 min. followed by addition oftert-butylchlorodimethylsilane (2.56 g, 16.95 mmol). The crude waspurified via flash column chromatography (100% in hexane) to give(4-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane as a clear oil(4.45 g, 99%): ¹HNMR (CDCl₃) δ 6.95 (s, wide, 1H, Ar), 6.92 (d, J=2 Hz,1H, Ar), 6.71 (d, J=7 Hz, 1H, Ar), 3.79 (s, 3H, OCH₃), 0.98 (s, 9H,3CH₃), 0.13 (s, 6H, 2CH₃). The product was carried over to the nextstep.

(4-bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (4.37 g, 13.77mmol), n-butyl lithium (5.51 ml, 13.77 mmol), and3,5-dimethoxybenzaldehyde (2.08 g, 12.52 mmol) were treated in the samemanner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (5% EtOAc in hexanegradient to 20% EtOAc in hexane in about 40 min.) to give[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanola clear oil (3.94 g, 78%): ¹HNMR (CDCl₃) δ 6.89 (s, wide, 1H, Ar), 6.78(s, wide, 2H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar),5.69 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 3H, OCH₃), 3.76 (s, 6H, 20CH₃),2.19 (d, J=3 Hz, 1H, OH), 0.98 (s, 9H, 3CH₃), 0.14 (s, 6H, 2CH₃). Theproduct was carried over to the next step.

[4-(tert-Butyldimethylsilanyloxy)-3-methoxyphenyl]-(3,5-dimethoxyphenyl)methanol(3.90 g, 9.64 mmol) and activated MnO₂ powder (8.1 g, 93 mmol) weretreated in the same manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The product[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanonewas a light yellow oil (3.69 g, 95%): ¹HNMR (CDCl₃) δ 7.47 (d, J=I Hz,1H, Ar), 7.31 (dd, J=I Hz and 7 Hz, 1H, Ar), 6.87 (m, 3H, Ar), 6.65 (t,J=2 Hz, 1H, Ar), 3.87 (s, 3H, single OCH₃ group), 3.83 (s, 6H, 20CH₃),1.01 (s, 9H, 3CH₃), 0.20 (s, 6H, 2CH₃). The product was carried over tothe next step.

[4-(tert-Butyldimethylsilanyloxy)-3-methoxyphenyl]-(3,5-dimethoxyphenyl)methanone(3.64 g, 9.04 mmol), cyanomethylphosphonic acid diethyl ester (2.85 ml,18.08 mmol) in anhydrous THF (10 ml), and lithiumbis(trimethylsilyl)amide (1.0 M solution in THF, 18.08 ml, 18.08 mmol)were treated in the same manner as described above for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified via flash column chromatography (5% EtOAc in hexanegradient to 20% EtOAc in hexane in about 30 min.) to give3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrileas a white solid (3.00 g, 78%). The product was carried over to the nextstep without further purification.

Tetrabutylammonium fluoride (1.0 M solution in THF, 5.55 ml, 5.55 mmol)was added at rt to a stirred solution of3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile(1.97 g, 4.63 mmol) in THF (35 ml). The colorless clear solutionimmediately turned into brown/red wine color. The reaction should bedone within one hour. Ice water (15 ml) was poured into the reddishsolution, followed by addition of ether (80 ml). The mixture was washedwith water (2×100 ml), dried over MgSO₄, filtered and concentrated to ayellow oil, which was lyophilized to give3-(3,5-dimethoxy-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-acrylonitrile asa white gummy solid (1.26 g, 88%): mp, 120-122° C.; ¹HNMR (DMSO-d₆) δ9.68 (s, 1H, OH group of one isomer), 9.60 (s, 1H, OH group of the otherisomer), 7.11-6.61 (m, 8H, Ar), 6.49-6.46 (m, 4H, Ar), 6.23 (s, 1H,double bond proton of one isomer), 6.11 (s, 1H, double bond proton ofthe other isomer), 3.78-3.74 (multiple singlets, 18H, 60CH₃), isomerratio based on ¹HNMR was 49%:51%; ¹³C NMR (CDCl₃) δ 163.0, 162.9, 160.9,160.8, 148.2, 147.7, 146.6, 146.3, 141.6, 139.2, 130.9, 128.9, 124.2,122.9, 118.5, 118.2, 114.6, 114.5, 112.3, 110.6, 107.9, 107.2, 102.3,102.2, 93.7, 93.1, 56.4, 56.2, 55.7, 55.6; Anal. Calcd. For C₁₈H₁₇NO₄:C, 69.44; H, 5.50; N, 4.50. Found: C, 69.24; H, 5.38; N, 4.27.

4.6.2.603-(3-Amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(E and Z isomers)

(4-Methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol wasprepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing 3-ethoxy-4-methoxy-bromobenzene (7.6 g, 33 mmol), magnesiumturning (0.8 g, 33 mmol) and 4-methoxy-3-nitro-benzaldehyde (5.0 g, 27.6mmol). The crude product was purified by flash chromatography (silicagel, CH₂Cl₂: EtOAc 9:1) to afford(4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (3.9 g,42%): ¹H NMR (CDCl₃) δ 7.88 (d, J=2 Hz, 1H), 7.53-7.49 (dd, J=3, 9 Hz,1H), 7.05 (d, J=8 Hz, 1H), 6.84 (s, 3H), 5.75 (d, J=3 Hz, 1H), 4.01 (m,2H), 3.94 (s, 3H), 3.86 (s, 3H), 2.30 (d, J=3 Hz, 1H), 1.44 (t, 3H).

(4-Methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone wasprepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol(3.9 g, 11.6 mmol) and pyridinium chlorochromate (3.7 g, 17.4 mmol). Thecrude product was purified by flash chromatography (silica gel, CH₂Cl₂:EtOAc 95:5) to afford(4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone (3.4 g,89%) as an orange solid: ¹H NMR (CDCl₃) δ 8.28 (d, J=2 Hz, 1H),8.06-8.02 (dd, J=3, 8.7 Hz, 1H), 7.41 (d, J=1 Hz, 1H), 7.31-7.26 (dd,J=2, 8.4 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.21-4.12(q, J=7 Hz, 2H), 4.05 (s, 3H), 3.96 (s, 3H), 1.50 (t, J=6 Hz, 3H).

3-(4-Methoxy-3-nitro-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrilewas prepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (4-methoxy-3-nitro-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone(3.4 g, 10.3 mmol), lithium bis(trimethylsilyl)amide (11.3 mL, 11.3mmol) and diethyl cyanomethylphosphate (2.0 g, 11.3 mmol). The crudeproduct was purified by flash chromatography (silica gel, Hexane: CH₂Cl₂3:97) to afford a mixture of isomers of3-(4-methoxy-3-nitro-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(3.4 g, 95%) as a yellow solid: ¹H NMR (CDCl₃) δ 7.85-7.77 (m, 1H),7.54-6.78 (m, 5H), 5.67 (5.59) (s, 1H), 4.10-4.00 (m, 5H), 3.93 (s, 3H),1.49-1.42 (m, 3H).

A suspension of3-(4-methoxy-3-nitro-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(3.3 g, 9.7 mmol) and tin chloride dihydrate (11.6 g, 51.8 mmol) inethanol (70 mL) was heated at 70° C. oil bath for 1 h then cooled toroom temperature. The mixture was poured into ice (200 mL), and the pHwas made strongly alkaline by the addition of ION NaOH. The mixture wasextracted with EtOAc (5×50 mL). The combined extracts were washed withwater (40 mL), brine (40 mL) and dried (MgSO⁴). Solvent was removed andthe crude product was purified by flash chromatography (silica gel,Hexane: EtOAc 7:3) to afford mixture of isomers of3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile(1.1 g, 33%) as a yellow solid: mp 141-143° C.; ¹H NMR (CDCl₃) δ7.00-6.64 (m, 6H), 5.49 (d, 1H), 4.12-3.98 (m, 2H), 3.92-3.88 (m, 8H),1.47-1.40 (m, 3H); ¹³C NMR (CDCl₃) δ 162.95, 151.23, 150.70, 146.70,148.03, 147.81, 136.11, 135.93, 132.1 1, 129.90, 129.80, 123.07, 122.10,120.72, 119.62, 118.89, 118.81, 115.99, 114.66, 114.23, 112.97, 110.90,109.81, 55.59, 55.52, 14.67; Anal Calcd for C₁₉H₂₀N₂O₃: C, 70.35; H,6.21; N, 8.64. Found: C, 70.25; H, 6.21; N, 8.46.

4.6.2.613-(4-Amino-3-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers)

(3-Methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol was preparedanalogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing 3,4-bromoveratrole (2.5 g, 11.5 mmol), magnesium turning (0.3 g,11.5 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.5 g, 8.2 mmol). Thecrude product was purified by flash chromatography (silica gel, CH₂Cl₂:EtOAc 9:1) to afford(3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (1.9 g, 72%):¹H NMR (CDCl₃) δ 7.80 (d, J=8 Hz, 1H), 7.22 (s, 1H), 6.98-6.85 (m, 4H),5.79 (d, J=2 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 6H).

A suspension of(3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (1.9 g, 6.0mmol) and MnO₂ (9.1 g, 104.7 mmol) in CH₂Cl₂ (100 mL) was stirred for 2days. The mixture was filtered through Celite and the Celite was washedwith CH₂Cl₂. The filtrate was concentrated and the residue was purifiedby flash chromatography (silica gel, CH₂Cl₂: EtOAc 95:5) to afford(3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (1.2 g, 64%)of yellow solid: ¹H NMR (CDCl₃) δ 7.87 (d, J=8 Hz, 1H), 7.50-7.46 (dd,J=2, 5.7 Hz, 2H), 7.36-7.30 (m, 2H), 6.93 (d, J=8 Hz, 1H), 4.01 (s, 3H),3.98 (s, 3H), 3.96 (s, 3H).

3-(3-Methoxy-4-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile wasprepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (3-methoxy-4-nitro-phenyl)-(3,4-diemthoxy-phenyl)-methanone (1.2g, 3.8 mmol), lithium bis(trimethylsilyl)amide (4.2 mL, 4.2 mmol) anddiethyl cyanomethylphosphate (0.7 g, 4.2 mmol). The crude product waspurified by flash chromatography (silica gel, Hexane: EtOAc 1:1) toafford3-(3-methoxy-4-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (1.2g, 91%): ¹H NMR (CDCl₃) δ 7.89 (d, J=8 Hz, 1H), 7.21 (d, J=1 Hz, 1H),7.05 (dd, J=2, 8.4 Hz, 1H), 6.85 m, 3H), 5.79 (s, 1H), 3.98-3.86 (m 9H).

3-(4-Amino-3-methoxy-phenyl)-3-(3,4-diemthoxy-phenyl)-acrylonitrile wasprepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrileusing3-(3-methoxy-4-nitro-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (1.2g, 3.4 mmol) and tin chloride dihydrate (4.2 g, 18.0 mmol). The crudeproduct was purified by flash chromatography (silica gel, Hexane: EtOAc7:3) to afford a mixture of isomers of3-(4-amino-3-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile (0.7g, 64%) as a yellow solid: mp 104-106° C.; ¹H NMR (CDCl₃) δ 7.00-6.63 (m6H), 5.52 (5.43)(s, 1H), 4.10 (s, 2H), 3.95-3.80 (m, 9H); ¹³C NMR(CDCl₃) δ 185.55, 183.98, 162.98, 150.83, 148.69, 148.52, 146.37,138.97, 138.53, 135.76, 132.51, 129.30, 128.81, 123.95, 123.16, 122.80,122.23, 119.17, 113.78, 112.93, 112.02, 111.81, 110.69, 110.37, 90.28,90.18, 90.02, 55.97, 55.90, 55.54; Anal Calcd for C₁₈H₁₈N₂O₃: C, 69.66;H, 5.85; N, 9.03. Found: C, 69.59; H, 5.81; N, 8.95.

4.6.2.623-(4-Amino-3-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers)

(3-Methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was preparedanalogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing 3,5-dimethoxy-bromobenzene (4.4 g, 20.1 mmol), magnesium turning(1.0 g, 20.1 mmol) and 3-methoxy-4-nitro-benzaldehyde (3.0 g, 16.8 mmol)to afford (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol(3.9 g, 73%): ¹H NMR (CDCl₃) δ 7.79 (d, J=8 Hz, 1H), 7.22 (s, 1H),7.00-6.99 (dd, J=2, 9.1 Hz, 1H), 6.48 (d, J=2 Hz, 2H), 6.40 (d, J=2 Hz,1H), 5.75 (d, J=3 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 6H), 2.45 (d, J=2 Hz,1H).

A suspension of(3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.9 g, 12.3mmol) and MnO₂ (8.5 g, 98.4 mmol) in CH₂Cl₂ (100 mL) was stirred for 3days. The mixture was filtered through Celite and the Celite was washedwith CH₂Cl₂. The filtrate was concentrated to afford(3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.7 g,94%): ¹H NMR (CDCl₃) δ 7.85 (d, J=8 Hz, 1H), 7.52 (d, J=0.9 Hz, 1H),7.39-7.35 (dd, J=2, 9.6 Hz, 1H), 6.89 (d, J=2 Hz, 2H), 6.71 (d, J=2 Hz,1H), 4.01 (s, 3H), 3.83 (s, 6H).

3-(3-Methoxy-4-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (Eand Z isomers) was prepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrileusing (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.7g, 11.5 mmol), lithium bis(trimethylsilyl)amide (12.7 mL, 12.7 mmol) anddiethyl cyanomethylphosphate (2.5 g, 12.7 mmol) to afford mixture ofisomers of3-(3-methoxy-4-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (3.9g, 99%): ¹H NMR (CDCl₃) δ 7.91-7.82 (m, 1H), 7.26-7.22 (m, 1H),7.04-6.98 (m, 2H), 6.59-6.53 (m, 2H), 6.38-6.37 (m, 1H), 5.85(5.77) (s,1H), 4.00-3.91 (m, 3H), 3.83-3.78 (m 6H).

3-(4-Amino-3-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile wasprepared analogously to3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrileusing3-(3-methoxy-4-nitro-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (3.9g, 11.5 mmol) and tin chloride dihydrate (12.8 g, 58.0 mmol) to affordmixture isomers of3-(4-amino-3-methoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (3.1g, 84%) as a yellow solid: mp 114-116° c; ¹H NMR (CDCl₃) δ 7.04-6.45 (m,6H), 5.60(5.46) (s, 1H), 3.86-3.70(m, 11H); ¹³CNMR(CDCl₃)δ 163.18,162.98, 160.57, 146.32, 142.06, 139.34, 139.07, 138.57, 128.03, 126.37,124.00, 122.74, 107.15, 102.02, 101.95, 91.86, 90.98, 55.69, 55.55; AnalCalcd for C₁₈H₁₈N₂O₃: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.33; H,5.67; 8.85.

4.6.2.63 3-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-acrylonitrile

(3-Cyclopentyloxy-4-methoxy-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol),cyanomethylphosphonic acid diethyl ester (0.3 ml, 1.9 mmol) in anhydrousTHF (10 ml), and lithium bis(trimethylsilyl)amide (1.3 M solution inTHF, 1.4 ml, 1.9 mmol) were treated in the same manner as describedabove for the synthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified by flash column chromatography to give3-(3-cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-acrylonitrile as a solid(0.41 g, 76%): mp, 90.6-93° C.; ¹H NMR (CDCl₃) δ 7.54-7.24 (m, 10H),7.05-6.73 (m, 6H), 5.66 (s, 1H), 5.60 (s, 1H), 4.81-4.62 (m, 2H), 3.89(s, 3H), 3.87 (s, 3H), 2.00-1.45 (m, 16H); ¹³C NMR (CDCl₃) δ 162.8,162.8, 152.2, 151.6, 147.4, 147.3, 139.5, 137.2, 130.2, 129.9, 129.6,129.3, 128.7, 128.5, 128.4, 123.0, 121.8, 118.4, 118.3, 116.1, 114.8,111.3, 93.2, 92.7, 80.6, 56.0, 32.8, 32.7, 24.1, 24.0; Anal. Calcd. ForC₂₁H₂₁NO₂: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.85; H, 6.59; N,4.31.

4.6.2.643-(3,4-Dimethoxy-phenyl)-3-(3,4,5-trimethoxy-Phenyl)-acrylonitrile

(3,4-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (3.3 g, 10mmol), cyanomethylphosphonic acid diethyl ester (2.4 ml, 15 mmol) inanhydrous THF (50 ml), and potassium bis(trimethylsilyl)amide (3.0 g, 15mmol) were treated in the same manner as described above for thesynthesis of3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crudewas purified by flash column chromatography to give3-(3,4-dimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as asolid (2.7 g, 77%): mp, 119-121° C.; ¹H NMR (DMSO-d₆)

7.14-7.07 (m, 1H), 7.00-6.77 (m, 2H), 6.66 (d, J=3 Hz, 2H), 6.25 (s,0.5H), 6.19 (s, 0.5H), 3.84-3.71 (m, 15H); ¹³C NMR (DMSO-d₆) □ 161.38,161.31, 152.65, 150.99, 150.14, 148.64, 148.18, 139.44, 138.44, 133.69,132.47, 130.01, 128.88, 122.66, 122.43, 118.66, 118.62, 112.75, 111.31,111.22, 110.94, 106.88, 106.27, 94.23, 93.53, 60.08, 56.02, 55.98,55.60, 55.55, 55.48; Anal. Calcd. For C₂₀H₂₁NO₅: C, 67.59; H, 5.96; N,3.94. Found: C, 67.66; H, 5.98; N, 3.88.

Equivalents:

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described will become apparent to thoseskilled in the art from the foregoing description. Such modificationsare intended to fall within the scope of the appended claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

1. A compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(c) andR_(d) is independently —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₅)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₃ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen,cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₅)₂, —OC(O)—R₁₀, —OC(O)—R₁₀, —N(R₁₀)₂,—C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,—NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₄ is substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₅ is substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂,—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₇ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₀₅—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) or with R₇, together form—O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; each occurrence of R₉ isindependently —H, substituted or unsubstituted lower alkyl, orsubstituted or unsubstituted cycloalkyl; each occurrence of R₁₀ isindependently substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen to which itis attached form a substituted or unsubstituted heterocycle, or R₁₀ is—H where appropriate; and each occurrence of R₁₆ and R₁₇ isindependently —H or halogen.
 2. A compound of claim 1, wherein R₃, R₄and R₅ are alkoxy.
 3. A compound of claim 2, wherein R₃, R₄ and R₅ aremethoxy.
 4. A compound of claim 2, wherein R₇ and R₈ are alkoxy.
 5. Acompound of claim 2, wherein R₆, R₇ and R₈ are alkoxy.
 6. A compound ofclaim 1, wherein R₁ is —H and R₂ is —CN.
 7. A compound of claim 1,wherein R₁ is —CN and R₂ is —H.
 8. A compound of claim 1, wherein thecompound is the E isomer.
 9. A compound of claim 1, wherein the compoundis the Z isomer.
 10. A compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with R_(a), together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; R₄ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₆ is substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₇ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₅)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂, or R₈ with R_(a), together form —O—C(R₁₆R)₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; each occurrence of R₉ is independently —H,substituted or unsubstituted lower alkyl, or substituted orunsubstituted cycloalkyl; each occurrence of R₁₀ is independentlysubstituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen to which it isattached form a substituted or unsubstituted heterocycle, or R₁₀ is —Hwhere appropriate; and each occurrence of R₁₆ and R₁₇ is independently—H or halogen.
 11. A compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(₁ 0)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; eachoccurrence of R₉ is independently —H, substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached form a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; each occurrence of R₁₆ andR₁₇ is independently —H or halogen; and with the proviso that if one ofR₃ or R₅ is H, then the other is not substituted or unsubstituted loweralkyl or substituted or unsubstituted alkoxy and if one of R₆ or R₈ isH, then the other is not substituted or unsubstituted lower alkyl orsubstituted or unsubstituted alkoxy.
 12. A compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀ ₀—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; eachoccurrence of R₉ is independently substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached formi a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; each occurrence of R₁₆ andR₁₇ is independently —H or halogen; and with the proviso that at leastone of R₄ and R₇ is —OPO(OH)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,—C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,—NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂.
 13. A compound having theformula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(RO)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; eachoccurrence of R₉ is independently —H, substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached form a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; each occurrence of R₁₆ andR₁₇ is independently —H or halogen; and wherein at least one of R₃, R₄,R₅, R₆, R₇, R₈, R_(a), R_(b), R_(c) or R_(d) is —OPO(OH)₂,—OC(O)—R₁₀—N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂.
 14. A compound having theformula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower atkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; eachoccurrence of R₉ is independently —H, substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached form a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; each occurrence of R₁₆ andR₁₇ is independently —H or halogen; and wherein at least one R_(a) andR_(b) and at least one of R_(c) and R_(d) is other than —H.
 15. Acompound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈with either R_(c) or with R₇, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; each occurrence of R₉ is independently —H,substituted or unsubstituted lower alkyl, or substituted orunsubstituted cycloalkyl; each occurrence of R₁₀ is independentlysubstituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen to which it isattached form a substituted or unsubstituted heterocycle, or R₁₀ is —Hwhere appropriate; each occurrence of R₁₆ and R₁₇ is independently —H orhalogen; and wherein either R₃ with either R_(a) or with R₄, togetherform —O—(C(R₁₆R₁₇))₂—O— or R₈ with either R_(c) or with R₇, togetherform —O—(C(R₁₆R₁₇))₂—O—.
 16. A compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —CN, substituted or unsubstitutedlower alkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, —COOH, —C(O)-lower alkyl, —C(O)O-lower alkyl,—C(O)—N(R₉)₂, substituted or unsubstituted aryl, or substituted orunsubstituted heterocycle; each occurrence of R_(a), R_(b), R_(c) andR_(d) is independently —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₃ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃ with either R_(a) orwith R₄, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; R₄ is —H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen,cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,—C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,—NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₅)₂) or —NHC(O)—R₁₀—NH₂; R₅ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R 0)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₆ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₇ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) or with R₇, together form—O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; each occurrence of R₉ isindependently —H, substituted or unsubstituted lower alkyl, orsubstituted or unsubstituted cycloalkyl; and each occurrence of R₁₀ isindependently substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen to which itis attached form a substituted or unsubstituted heterocycle, or R₁₀ is—H where appropriate.
 17. A compound or a pharmaceutically acceptablesalt, hydrate or solvate thereof having the structure:


18. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable carrier.
 19. The pharmaceuticalcomposition of claim 18, wherein said composition is suitable forparenteral, transdermal, mucosal, nasal, buccal, rectal, sublingual, ororal administration to a subject.
 20. A method for inhibitingangiogenesis, said method comprising administering to a subject in needthereof a dose of an effective amount of the compound of claim
 1. 21. Amethod for inhibiting or reducing tubulin polymerization or tubulinstability in a cell, said method comprising contacting a cell with thecompound of claim
 1. 22. The method of claim 21 wherein the cell is acancerous cell
 23. A method for inhibiting PDE4 activity in a cell, saidmethod comprising contacting a cell with the compound of claim
 1. 24. Amethod for inhibiting or reducing tubulin polymerization or tubulinstability in a cell and inhibiting PDE4 activity in a cell, said methodcomprising contacting a cell with the compound of claim
 1. 25. A methodfor treating or ameliorating an inflammatory disorder comprisingadministering to a subject in need thereof an effective amount of thecompound of claim
 1. 26. A method for treating or ameliorating cancercomprising administering to a subject in need thereof an effectiveamount of the compound of claim
 1. 27. A method for inhibiting cancercell proliferation comprising contacting a cancer cell with an effectiveamount of the compound of claim
 1. 28. A method for inhibiting theproliferation of a multi-drug resistant cancer cell comprisingcontacting a multi-drug resistant cancer cell with an effective amountof the compound of claim
 1. 29. A method for targeting, blocking ordestroying the function of tumor vasculature, said method comprisingcontacting a tumor with an effective amount of a compound of claim 1.30. A method for targeting, blocking or destroying the endothelium oftumor vessels, said method comprising contacting a tumor with aneffective amount of a compound of claim
 1. 31. A method for targeting,blocking or destroying the function of tumor vasculature and inhibitingangiogenesis in a tumor, said method comprising contacting a tumor withan effective amount of a compound of claim
 1. 32. A method for treatingor ameliorating a central nervous system disorder comprisingadministering to a subject in need thereof an effective amount of acompound of claim
 1. 33. The method of claim 32, wherein the centralnervous system disorder is Parkinson's disease; bradykinesia; musclerigidity; parkinsonian tremor; parkinsonian gait; motion freezing;depression; defective long-term memory, Rubinstein-Taybi syndrome (RTS);dementia; a sleep disorder; postural instability; a hypokineticdisorder; inflammation; a synuclein disorder; multiple system artrophy;striatonigral degeneration; olivopontocerebellar atrophy; Shy-Dragersyndrome; motor neuron disease with parkinsonian features; Lewy bodydementia; a Tau pathology disorder; progressive supranculear palsy;corticobasal degeneration; frontotemporal dementia; an amyloid pathologydisorder; mild cognitive impairment; Alzheimer disease; Alzheimerdisease with parkinsonism; a genetic disorder with parkinsonianfeatures; Wilson disease; Hallervorden-Spatz disease; Chediak-Hagashidisease; SCA-3 spinocerebellar ataxia; X-linked dystonia parkinsonism;Huntington disease; prion disease; a hyperkinetic disorder; chorea;ballismus; a dystonia tremor; Amyotrophic Lateral Sclerosis (ALS); CNStrauma or myoclonus.
 34. A method for treating or ameliorating arefractory cancer comprising administering to a subject in need thereofan effective amount of a compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower alkyl,—C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl; R₄ is —H, —NO₂, cyano,substituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, halogen, —OH, —C(O)(R₁₀)₂, —COOH, —NH₂, —OC(O)—N(R₁₀)₂; R₅ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, or substituted or unsubstituted alkenyl; X is substituted orunsubstituted phenyl, substituted or unsubstituted pyridine, substitutedor unsubstituted pyrrolidine, substituted or unsubstituted imidizole,substituted or unsubstituted naphthalene, substituted or unsubstitutedthiophene, or substituted or unsubstituted cycloalkyl; each occurrenceof R₉ is independently —H or substituted or unsubstituted lower alkyl;and each occurrence of R₁₀ is independently —H or substituted orunsubstituted lower alkyl.
 35. The method of claim 34, wherein thecompound is the E isomer.
 36. The method of claim 34, wherein thecompound is the Z isomer
 37. The method of claim 34, wherein the canceris refractory to colchicine, a taxane or a vinca alkaloid.
 38. A methodfor treating or ameliorating a multi-drug resistant cancer comprisingadministering to a subject in need thereof an effective amount of acompound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower alkyl,—C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl; R₄ is —H, —NO₂, cyano,substituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, halogen, —OH, —C(O)(R₁₀)₂, —COOH, —NH₂, —OC(O)—N(R₁₀)₂; R₅ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, or substituted or unsubstituted alkenyl; X is substituted orunsubstituted phenyl, substituted or unsubstituted pyridine, substitutedor unsubstituted pyrrolidine, substituted or unsubstituted imidizole,substituted or unsubstituted naphthalene, substituted or unsubstitutedthiophene, or substituted or unsubstituted cycloalkyl; each occurrenceof R₉ is independently —H or substituted or unsubstituted lower alkyl;and each occurrence of R₁₀ is independently —H or substituted orunsubstituted lower alkyl.
 39. The method of claim 38, wherein thecompound is the E isomer.
 40. The method of claim 38, wherein thecompound is the Z isomer.
 41. The method of claim 38, wherein the canceris resistant to colchicine, a taxane or a vinca alkaloid.
 42. A methodfor treating or ameliorating a refractory cancer comprisingadministering to a subject in need thereof an effective amount of acompound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀, —N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀,—NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂, or R₃ with either R_(a) or with R₄, together form—O—C(R, ₆R] ₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀, —NH₂; R₅ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₇ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₈ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈with either RC or with R₇, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; each occurrence of R₉ is independently —H,substituted or unsubstituted lower alkyl, or substituted orunsubstituted cycloalkyl; each occurrence of R₁₀ is independentlysubstituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted lower hydroxyalkyl, or R₁₀ and a nitrogen to which it isattached form a substituted or unsubstituted heterocycle, or R₁₀ is —Hwhere appropriate; and each occurrence of R₁₆ and R₁₇ is independently—H or halogen.
 43. The method of claim 42, wherein the compound is the Eisomer.
 44. The method of claim 42, wherein the compound is the Zisomer.
 45. The method of claim 42, wherein the cancer is refractory tocolchicine, a taxane or a vinca alkaloid.
 46. A method for treating orameliorating a multi-drug resistant cancer comprising administering to asubject in need thereof an effective amount of a compound having theformula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁₇)—O— or—O—(C(R₁₆R₁₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀, —NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₀)₂, —C(O)N(RO)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁ ₇)—O— or —O—(C(R₁₆R₁ ₇))₂—O—; eachoccurrence of R₉ is independently —H, substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached form a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; and each occurrence of R₁₆and R₁₇ is independently —H or halogen.
 47. The method of claim 46,wherein the compound is the E isomer.
 48. The method of claim 46,wherein the compound is the Z isomer.
 49. The method of claim 46,wherein the cancer is resistant to colchicine, a taxane or a vincaalkaloid.
 50. The method of claim 26, 34, 38, 42 or 46, wherein thecancer is of the head, neck, eye, mouth, throat, esophagus, chest, bone,lung, colon, rectum, stomach, prostate, breast, ovaries, kidney, liver,pancreas or brain.
 51. A method for treating leukemia, fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, orretinoblastoma comprising administering to a subject in need thereof aneffective amount of a compound having theformula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower alkyl,—C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl; R₄ is —H, —NO₂, cyano,substituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, halogen, —OH, —C(O)(R₁₀)₂, —COOH, —NH₂, —OC(O)—N(R₁₀)₂; R₅ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, or substituted or unsubstituted alkenyl; X is substituted orunsubstituted phenyl, substituted or unsubstituted pyridine, substitutedor unsubstituted pyrrolidine, substituted or unsubstituted imidizole,substituted or unsubstituted naphthalene, substituted or unsubstitutedthiophene, or substituted or unsubstituted cycloalkyl; each occurrenceof R₉ is independently —H or substituted or unsubstituted lower alkyl;and each occurrence of R₁₀ is independently —H or substituted orunsubstituted lower alkyl.
 52. The method of claim 26, 34, 38, 42 or 46further comprising administering to said subject an effective amount ofone or more additional anti-cancer agents.
 53. The method of claim 52,wherein at least one of the anti-cancer agents is taxol, taxotere,cisplatin, carboplatin, oxaliplatin, doxorubicin, gemcitabine,capecitabine, 5-fluorouracil, etoposide, cyclophosphamide, vincristine,vinblastine, topotecan or irinotecan.
 54. The method of claim 52,wherein at least one of the anti-cancer agents is an anti-angiogenicagent, a vascular targeting agent, an immunomodulatory agent or ananti-inflammatory agent.
 55. The method of claim 26, 34 or 42, whereinsaid cancer is refractory to chemotherapy or radiation therapy.
 56. Themethod of claim 25, wherein the inflammatory disorder is asthma,encephilitis, inflammatory bowel disease, hepatitis, chronic obstructivepulmonary disease (COPD), idiopathic pulmonary fibrosis, arthritis,vasculitis, an allergic disorder, acute obstructive pulmonary disease,Crohn's Disease, Bechet's Disease, HSP, colitis, or inflammation due toreperfusion.
 57. The method of claim 25 further comprising administeringto said subject an effective amount of one or more anti-inflammatoryagents.
 58. The method of claim 57, wherein at least one of theanti-inflammatory agents is an antihistamine, a non-steroidalanti-inflammatory drug or a steroid.
 59. The method of claim 26, 34, 38,42 or 46, wherein the compound is administered parenterally,transdermally, mucosally, nasally, buccally, rectally, sublingually, ororally.
 60. The method of claim 26, 34, 38, 42 or 46, wherein thesubject is human.
 61. A method for treating a central nervous systemdisorder comprising administering to a patient in need thereof aneffective amount of a compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower alkyl,—C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl; R₄ is —H, —NO₂, cyano,substituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, halogen, —OH, —C(O)(R₁₀)₂, —COOH, —NH₂, —OC(O)—N(R₁₀)₂; R₅ issubstituted or unsubstituted lower alkyl, substituted or unsubstitutedalkoxy, or substituted or unsubstituted alkenyl; X is substituted orunsubstituted phenyl, substituted or unsubstituted pyridine, substitutedor unsubstituted pyrrolidine, substituted or unsubstituted imidizole,substituted or unsubstituted naphthalene, substituted or unsubstitutedthiophene, or substituted or unsubstituted cycloalkyl; each occurrenceof R₉ is independently —H or substituted or unsubstituted lower alkyl;and each occurrence of R₁₀ is independently —H or substituted orunsubstituted lower alkyl.
 62. A method for treating a central nervoussystem disorder comprising administering to a patient in need thereof aneffective amount of a compound having the formula:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: R₁ and R₂ are independently —H, —CN, substituted orunsubstituted lower alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, —COOH, —C(O)-lower alkyl,—C(O)O-lower alkyl, —C(O)—N(R₉)₂, substituted or unsubstituted aryl, orsubstituted or unsubstituted heterocycle; each occurrence of R_(a),R_(b), R_(c) and R_(d) is independently —H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, halogen, cyano, —NO₂, —OH,—OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀, —N(R₁₀)₂, —NHC(O)CH(R₁ O)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₃ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃with either R_(a) or with R₄, together form —O—C(R₁₆R₁ ₇)—O— or —O—(C(R₁₆R₁ ₇))₂—O—; R₄ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₅)₂) or —NHC(O)—R₁₀, —NH₂; R₅ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₆ is —H, substituted orunsubstituted lower alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, —NO₂,—OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂,—NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂,—NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or—NHC(O)—R₁₀—NH₂; R₇ is —H, substituted or unsubstituted lower alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂,—OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀,—S(O)₂—R₁₀, —NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀,—NHC(O)—R₁₀—N(R₁₀)₂, —NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂; R₈ is—H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀—NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—; eachoccurrence of R₉ is independently —H, substituted or unsubstituted loweralkyl, or substituted or unsubstituted cycloalkyl; each occurrence ofR₁₀ is independently substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀ and anitrogen to which it is attached form a substituted or unsubstitutedheterocycle, or R₁₀ is —H where appropriate; and each occurrence of R₁₆and R₁₇ is independently —H or halogen.